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Variant annotation and effect prediction package.
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package org.snpeff.vcf;
import java.util.ArrayList;
import java.util.HashMap;
import java.util.Iterator;
import java.util.LinkedList;
import java.util.List;
import java.util.Map;
import java.util.Set;
import java.util.regex.Matcher;
import java.util.regex.Pattern;
import org.snpeff.align.VcfRefAltAlign;
import org.snpeff.fileIterator.VcfFileIterator;
import org.snpeff.interval.Cds;
import org.snpeff.interval.Chromosome;
import org.snpeff.interval.Marker;
import org.snpeff.interval.Variant;
import org.snpeff.interval.Variant.VariantType;
import org.snpeff.interval.VariantBnd;
import org.snpeff.snpEffect.LossOfFunction;
import org.snpeff.util.Gpr;
/**
* A VCF entry (a line) in a VCF file
* @author pablocingolani
*/
public class VcfEntry extends Marker implements Iterable {
public enum AlleleFrequencyType {
Common, LowFrequency, Rare
}
public static final String FILTER_PASS = "PASS";
public static final char WITHIN_FIELD_SEP = ',';
public static final String SUB_FIELD_SEP = ";";
public static final String[] EMPTY_STRING_ARRAY = new String[0];
public static final double ALLELE_FEQUENCY_COMMON = 0.05;
public static final double ALLELE_FEQUENCY_LOW = 0.01;
public static final Pattern INFO_KEY_PATTERN = Pattern.compile("[\\p{Alpha}_][\\p{Alnum}._]*");
public static final String VCF_INFO_END = "END"; // Imprecise variants
// In order to report sequencing data evidence for both variant and non-variant positions in the genome, the VCF
// specification allows to represent blocks of reference-only calls in a single record using the END INFO tag, an idea
// originally introduced by the gVCF file format. The convention adopted here is to represent reference evidence as
// likelihoods against an unknown alternate allele. Think of this as the likelihood for reference as compared to any
// other possible alternate allele (both SNP, indel, or otherwise). A symbolic alternate allele <*> is used to represent
// this unspecified alternate allele
public static final String VCF_ALT_NON_REF = "<*>"; // See VCF 4.2 section "5.5 Representing unspecified alleles and REF-only blocks (gVCF)"
public static final String VCF_ALT_NON_REF_gVCF = ""; // NON_REF tag for ALT field (only in gVCF fields)
public static final String VCF_ALT_MISSING_REF = "*"; // The '*' allele is reserved to indicate that the allele is missing due to a upstream deletion (see VCF 4.3 spec., ALT definition)
public static final String[] VCF_ALT_NON_REF_gVCF_ARRAY = { VCF_ALT_NON_REF_gVCF };
public static final String[] VCF_ALT_NON_REF_ARRAY = { VCF_ALT_NON_REF };
public static final String[] VCF_ALT_MISSING_REF_ARRAY = { VCF_ALT_MISSING_REF };
public static final String VCF_INFO_HOMS = "HO";
public static final String VCF_INFO_HETS = "HE";
public static final String VCF_INFO_NAS = "NA";
public static final String VCF_INFO_PRIVATE = "Private";
private static final Map INFO_VALUE_ENCODE;
private static final long serialVersionUID = 4226374412681243433L;
static {
// Initialize VCF value encoding table
INFO_VALUE_ENCODE = new HashMap<>();
// INFO_VALUE_ENCODE.put("%3A", ":"); // This is used in genotype entries, not INFO entries.
INFO_VALUE_ENCODE.put("%3B", ";");
INFO_VALUE_ENCODE.put("%3D", "=");
// INFO_VALUE_ENCODE.put("%25", "%");
INFO_VALUE_ENCODE.put("%2C", ",");
INFO_VALUE_ENCODE.put("%0D", "\n");
INFO_VALUE_ENCODE.put("%0A", "\r");
INFO_VALUE_ENCODE.put("%09", "\t");
}
protected String[] alts;
protected String altStr;
protected String chromosomeName; // Original chromosome name
protected String filter;
protected String format;
protected String formatFields[];
protected String genotypeFields[]; // Raw fields from VCF file
protected String genotypeFieldsStr; // Raw fields from VCF file (one string, tab separated)
protected byte genotypeScores[];
protected HashMap info;
protected String infoStr = "";
protected String line; // Line from VCF file
protected int lineNum; // Line number
protected Double quality;
protected String ref;
protected LinkedList variants;
protected List vcfEffects;
protected VcfFileIterator vcfFileIterator; // Iterator where this entry was red from
protected ArrayList vcfGenotypes = null;
/**
* Does 'value' represent an EMPTY / MISSING value in a VCF field?
* (or multiple MISSING comma-separated values)
*/
public static boolean isEmpty(String value) {
if (value == null || value.isEmpty() || value.equals(VcfFileIterator.MISSING)) return true;
if (value.indexOf(',') >= 0) {
// Multiple values, all of them MISSING?
String values[] = value.split(",");
for (String val : values)
if (!(val.isEmpty() || val.equals(VcfFileIterator.MISSING))) return false;
return true;
}
return false;
}
/**
* Make sure the INFO key matches the regular
* expression (as specified in VCF spec 4.3)
*/
public static boolean isValidInfoKey(String key) {
Matcher m = INFO_KEY_PATTERN.matcher(key);
return m.matches();
}
/**
* Check that this value can be added to an INFO field
* @return true if OK, false if invalid value
*/
public static boolean isValidInfoValue(String value) {
boolean invalid = ((value != null) && ((value.indexOf(' ') >= 0) || (value.indexOf(';') >= 0) || (value.indexOf('=') >= 0) || (value.indexOf('\t') >= 0) || (value.indexOf('\n') >= 0)));
return !invalid;
}
/**
* Decode INFO value
*/
public static String vcfInfoDecode(String str) {
if (str == null || str.isEmpty() || str.equals(".")) return str;
for (String encoded : INFO_VALUE_ENCODE.keySet())
str = str.replace(encoded, INFO_VALUE_ENCODE.get(encoded));
return str;
}
/**
* Encode a string to be used in an 'INFO' field value
* From the VCF 4.3 specification
* Characters with special meaning (such as field delimiters ';' in INFO or ':' FORMAT
* fields) must be represented using the capitalized percent encoding:
* %3A : (colon)
* %3B ; (semicolon)
* %3D = (equal sign)
* %25 % (percent sign)
* %2C , (comma)
* %0D CR
* %0A LF
* %09 TAB
*/
public static String vcfInfoEncode(String str) {
if (str == null || str.isEmpty() || str.equals(".")) return str;
for (String encoded : INFO_VALUE_ENCODE.keySet())
str = str.replace(INFO_VALUE_ENCODE.get(encoded), encoded);
return str.replaceAll(" ", "_"); // Transform spaces, if any
}
/**
* Return a string safe to be used in an 'INFO' field key
*/
public static String vcfInfoKeySafe(String str) {
if (str == null) return str;
str = str.replaceAll("[^a-zA-Z0-9_.]", "_");
char c0 = str.charAt(0);
if (c0 != '_' && !Character.isAlphabetic(c0)) str = '_' + str;
return str;
}
/**
* Return a string safe to be used in an 'INFO' field value
*/
public static String vcfInfoValueSafe(String str) {
if (str == null) return str;
return str.replaceAll("[ ,;|=()\t]", "_");
}
public VcfEntry(VcfFileIterator vcfFileIterator, Marker parent, String chromosomeName, int start, String id, String ref, String altsStr, double quality, String filterPass, String infoStr, String format) {
super(parent, start, start + ref.length() - 1, false, id);
this.chromosomeName = chromosomeName;
this.ref = ref;
parseAlts(altsStr);
this.quality = quality;
filter = filterPass;
this.infoStr = infoStr;
parseInfo();
this.format = format;
parseEnd(altsStr);
}
/**
* Create a line form a file iterator
*/
public VcfEntry(VcfFileIterator vcfFileIterator, String line, int lineNum, boolean parseNow) {
super(null, 0, 0, false, "");
this.vcfFileIterator = vcfFileIterator;
this.lineNum = lineNum;
this.line = line;
if (parseNow) parse();
}
/**
* Add string to FILTER field
*/
public void addFilter(String filterStr) {
// Get current value
if (filter.equals(".") || filter.equals(VcfEntry.FILTER_PASS)) filter = ""; // Empty?
// Append new value
filter += (!filter.isEmpty() ? ";" : "") + filterStr; // Add this filter to the not-passed list
}
/**
* Add a 'FORMAT' field
*/
public void addFormat(String formatName) {
if (format == null) format = "";
if (format.indexOf(formatName) >= 0) throw new RuntimeException("Format field '" + formatName + "' already exists!");
// Add to format
format += (format.endsWith(":") ? "" : ":") + formatName;
}
/**
* Add a genotype as a string
*/
public void addGenotype(String vcfGenotypeStr) {
if (vcfGenotypes == null) vcfGenotypes = new ArrayList<>();
if (format == null) format = "";
vcfGenotypes.add(new VcfGenotype(this, format, vcfGenotypeStr));
genotypeScores = null; // Reset or invalidate scores
}
/**
* Add a "key=value" tuple the info field
*
* @param key : INFO key name
* @param value : Can be null if it is a boolean field.
*/
public void addInfo(String key, String value) {
if (!isValidInfoKey(key)) throw new RuntimeException("Illegal INFO key / name. Key: \"" + key + "\" does not match regular expression ^[A-Za-z_][0-9A-Za-z_.]*$");
if (!isValidInfoValue(value)) throw new RuntimeException("No white-space, semi-colons, or equals-signs are permitted in INFO field values. Name:\"" + key + "\" Value:\"" + value + "\"");
// Remove previous 'key' for INFO field?
removeInfo(key);
// Is this a 'flag'?
boolean isFlag = false;
VcfHeader vcfHeader = vcfFileIterator.getVcfHeader();
if (vcfHeader != null) {
VcfHeaderInfo vcfHeaderInfo = vcfFileIterator.getVcfHeader().getVcfHeaderInfo(key);
isFlag = (vcfHeaderInfo != null) && (vcfHeaderInfo.getVcfInfoType() == VcfInfoType.Flag);
}
// Add to info hash (if available)
if (info != null) info.put(key, value);
// Append value to infoStr
String addInfoStr = key + (value != null && !isFlag ? "=" + value : ""); // String to append
if ((infoStr == null) || infoStr.isEmpty()) infoStr = addInfoStr;
else {
if (!infoStr.endsWith(SUB_FIELD_SEP)) infoStr += SUB_FIELD_SEP; // Do we need to add a semicolon?
infoStr += addInfoStr; // Add info string
}
}
/**
* Categorization by allele frequency
*/
public AlleleFrequencyType alleleFrequencyType() {
double maf = maf();
if (maf <= ALLELE_FEQUENCY_LOW) return AlleleFrequencyType.Rare;
if (maf <= ALLELE_FEQUENCY_COMMON) return AlleleFrequencyType.LowFrequency;
return AlleleFrequencyType.Common;
}
/**
* Is this entry heterozygous?
*
* Infer Hom/Her if there is only one sample in the file.
* Ohtherwise the field is null.
*/
public Boolean calcHetero() {
// No genotyping information? => Use number of ALT field
if (genotypeFieldsStr == null) return isMultiallelic();
Boolean isHetero = null;
// No genotype fields => Parse fields (we only parse them if there is only one GT field)
if (genotypeFields == null) {
// Are there more than two tabs? (i.e. more than one format field + one genotype field)
int countFields, fromIndex;
for (countFields = 0, fromIndex = 0; (fromIndex >= 0) && (countFields < 1); countFields++, fromIndex++)
fromIndex = genotypeFieldsStr.indexOf('\t', fromIndex);
// OK only one genotype field => Parse it in order to extract homo info.
if (countFields == 1) parseGenotypes();
}
// OK only one genotype field => calculate if it is heterozygous
if ((genotypeFields != null) && (genotypeFields.length == 1)) isHetero = getVcfGenotype(0).isHeterozygous();
return isHetero;
}
/**
* Perform several simple checks and report problems (if any).
*/
public String check() {
StringBuilder sb = new StringBuilder();
// Check REF
if (ref.indexOf(",") >= 0) sb.append("REF field has multiple entries (this is not allowed)\n");
// Check INFO fields
for (String infoName : getInfoKeys()) {
String err = checkInfo(infoName);
if (!err.isEmpty()) sb.append(err + "\n");
}
// Check genotypes
sb.append(checkGenotypes());
return sb.toString();
}
/**
* Check genotypes
*/
String checkGenotypes() {
StringBuilder err = new StringBuilder();
if (getVcfFileIterator() != null && getVcfFileIterator().getVcfHeader() != null) {
int numGt = getVcfGenotypes().size();
int numSamples = getVcfFileIterator().getVcfHeader().getNumberOfSamples();
if (numGt != numSamples) err.append("Number of genotypes (" + numGt + ") differs form the number of samples (" + numSamples + ")\n");
}
// Check that each genotype matches the number of alleles
int numAlts = getAlts().length;
int gtNum = 1;
for (VcfGenotype vgt : getVcfGenotypes()) {
int gts[] = vgt.getGenotype();
if (gts != null) {
for (int i = 0; i < gts.length; i++)
if (gts[i] > numAlts) err.append("Genotype number " + gtNum + " has genotype number '" + gts[i] + "', but there are only '" + numAlts + "' ALTs.\n");
}
gtNum++;
}
return err.toString();
}
/**
* Check info field
* Note: We report the first error we find
*/
String checkInfo(String infoName) {
if (infoName.isEmpty()) return "";
VcfHeaderInfo vcfInfo = getVcfInfo(infoName);
if (vcfInfo == null) return "Cannot find header for INFO field '" + infoName + "'";
// Split INFO value and match it to allele
String valsStr = getInfo(infoName);
if (valsStr == null) return ""; // INFO field not present, nothing to do
// Check values
String values[] = valsStr.split(",");
for (String val : values)
if (!VcfEntry.isValidInfoValue(val)) return "INFO field '" + infoName + "' has an invalid value '" + val + "' (no spaces, tabs, '=' or ';' are allowed)";
// Check number of INFO elements
if (vcfInfo.isNumberNumber() && vcfInfo.getNumber() != values.length) {
VcfInfoType type = vcfInfo.getVcfInfoType();
if (type == VcfInfoType.Flag && values.length == 1) ; // OK, flags must have one or zero values
else return "INFO filed '" + infoName + "' has 'Number=" + vcfInfo.getNumber() + "' in header, but it contains '" + values.length + "' elements.";
}
if (vcfInfo.isNumberAllAlleles() && values.length != (alts.length + 1)) return "INFO filed '" + infoName + "' has 'Number=R' in header, but it contains '" + values.length + "' elements when there are '" + alts.length + "' alleles (it should have '" + (alts.length + 1) + "' elements).";
if (vcfInfo.isNumberAllAlleles() && values.length != alts.length) return "INFO filed '" + infoName + "' has 'Number=A' in header, but it contains '" + values.length + "' elements when there are '" + alts.length + "' alleles.";
return "";
}
@Override
public Cds cloneShallow() {
throw new RuntimeException("Unimplemented!");
}
/**
* Compress genotypes into "HO/HE/NA" INFO fields
*/
public boolean compressGenotypes() {
if (getAlts().length > 1) return false;
StringBuilder homs = new StringBuilder();
StringBuilder hets = new StringBuilder();
StringBuilder nas = new StringBuilder();
// Add all genotype codes
int idx = 0;
for (VcfGenotype gen : getVcfGenotypes()) {
int score = gen.getGenotypeCode();
if (score == 0) {
; //Nothing to do
} else if (score < 0) nas.append((nas.length() > 0 ? "," : "") + idx);
else if (score == 1) hets.append((hets.length() > 0 ? "," : "") + idx);
else if (score == 2) homs.append((homs.length() > 0 ? "," : "") + idx);
else return false; // Cannot compress
idx++;
}
// Update INFO fields
if (homs.length() > 0) addInfo(VCF_INFO_HOMS, homs.toString());
if (hets.length() > 0) addInfo(VCF_INFO_HETS, hets.toString());
if (nas.length() > 0) addInfo(VCF_INFO_NAS, nas.toString());
// Nothing added? Add 'NAS' (as an indicator that it was compressed
if ((homs.length() == 0) && (hets.length() == 0) && (nas.length() == 0)) addInfo(VCF_INFO_NAS, null);
return true;
}
/**
* Remove a string from FILTER field
* @returns true if the value is removed
*/
public boolean delFilter(String filterStr) {
// Get current value
StringBuilder sbFilter = new StringBuilder();
// Split by semicolon and filter out the undesired values
boolean removed = false;
for (String f : filter.split(";")) {
if (!f.equals(filterStr)) sbFilter.append((sbFilter.length() > 0 ? ";" : "") + f); // Append if it does not match filterStr
else removed = true;
}
// Changed? Set new value
if (removed) filter = sbFilter.toString();
return removed;
}
/**
* Get index of matching ALT entry
* @return -1 if not found
*/
public int getAltIndex(String alt) {
for (int i = 0; i < alts.length; i++)
if (alts[i].equalsIgnoreCase(alt)) return i;
return -1;
}
public String[] getAlts() {
return alts;
}
/**
* Create a comma separated ALTS string
*/
public String getAltsStr() {
if (altStr != null) {
if (altStr.isEmpty()) return ".";
return altStr;
}
if (alts == null) return "";
StringBuilder sb = new StringBuilder();
for (String alt : alts)
sb.append(alt + " ");
altStr = sb.toString().trim().replace(' ', ',');
return altStr;
}
/**
* Original chromosome name (as it appeared in the VCF file)
*/
@Override
public String getChromosomeNameOri() {
return chromosomeName;
}
public String getFilter() {
return filter;
}
public String getFormat() {
return format;
}
public String[] getFormatFields() {
if (formatFields == null) {
if (format == null) formatFields = new String[0];
else formatFields = format.split(":");
}
return formatFields;
}
/**
* Return genotypes parsed as an array of codes
*/
public synchronized byte[] getGenotypesScores() {
if (genotypeScores != null) return genotypeScores;
// Not compressed? Parse codes
if (!isCompressedGenotypes()) {
List vcfGts = getVcfGenotypes();
int numSamples = vcfGts.size();
genotypeScores = new byte[numSamples];
int idx = 0;
for (VcfGenotype vcfGt : vcfGts)
genotypeScores[idx++] = (byte) vcfGt.getGenotypeCode();
return genotypeScores;
}
//---
// Uncompress (HO/HE/NA in info fields)
//---
// Get 'sparse' matrix entries
String hoStr = getInfo(VCF_INFO_HOMS);
String heStr = getInfo(VCF_INFO_HETS);
String naStr = getInfo(VCF_INFO_NAS);
// Parse 'sparse' entries
int numSamples = getNumberOfSamples();
genotypeScores = new byte[numSamples];
parseSparseGt(naStr, genotypeScores, -1);
parseSparseGt(heStr, genotypeScores, 1);
parseSparseGt(hoStr, genotypeScores, 2);
return genotypeScores;
}
/**
* Get info string
*/
public String getInfo(String key) {
if (info == null) parseInfo();
return info.get(key);
}
/**
* Get info string for a specific allele
*/
public String getInfo(String key, String allele) {
if (info == null) parseInfo();
// Get INFO value
String infoStr = info.get(key);
if (infoStr == null) return null;
// Split INFO value and match it to allele
String infos[] = infoStr.split(",");
// INFO fields having number type 'R' (all alleles) should have one value for reference as well.
// So in those cases we must skip the first value
int firstAltIndex = 0;
VcfHeaderInfo vcfInfo = getVcfInfo(key);
if (vcfInfo != null && vcfInfo.isNumberAllAlleles()) {
firstAltIndex = 1;
// Are we looking for 'REF' information?
if (ref.equalsIgnoreCase(allele)) return infos[0];
}
// Find ALT matching allele
for (int i = 0, j = firstAltIndex; (i < alts.length) && (j < infos.length); i++, j++)
if (alts[i].equalsIgnoreCase(allele)) return infos[j];
return null;
}
/**
* Get an INFO field matching a variant
* @returns Field value (string) or null if there is no match
*/
public String getInfo(String key, Variant var) {
if (info == null) parseInfo();
// Get INFO value
String infoStr = info.get(key);
if (infoStr == null) return null;
// Split INFO value and match it to allele
String infos[] = infoStr.split(",");
// INFO fields having number type 'R' (all alleles) should have one value for reference as well.
// So in those cases we must skip the first value
int firstAltIndex = 0;
VcfHeaderInfo vcfInfo = getVcfInfo(key);
if (vcfInfo != null && vcfInfo.isNumberAllAlleles()) {
firstAltIndex = 1;
// Are we looking for 'REF' information? I.e. variant is not a variant)
if (!var.isVariant()) return infos[0];
}
// Look for genotype matching 'var'
int i = firstAltIndex;
String gtPrev = "";
for (Variant v : variants()) {
if (i >= infos.length) break;
if (var.equals(v)) return infos[i];
if (!v.getGenotype().equals(gtPrev)) i++; // Advance genotype counter
}
return null;
}
/**
* Does the entry exists?
*/
public boolean getInfoFlag(String key) {
if (info == null) parseInfo();
return info.containsKey(key);
}
/**
* Get info field as a 'double' number
* The norm specifies data type as 'FLOAT', that is why the name of this method might be not intuitive
*/
public double getInfoFloat(String key) {
if (info == null) parseInfo();
String f = info.get(key);
if (f == null) return Double.NaN;
return Gpr.parseDoubleSafe(f);
}
/**
* Get info field as an long number
* The norm specifies data type as 'INT', that is why the name of this method might be not intuitive
*/
public long getInfoInt(String key) {
if (info == null) parseInfo();
String i = info.get(key);
if (i == null) return 0;
return Gpr.parseLongSafe(i);
}
/**
* Get all keys available in the info field
*/
public Set getInfoKeys() {
if (info == null) parseInfo();
return info.keySet();
}
/**
* Get the full (unparsed) INFO field
*/
public String getInfoStr() {
return infoStr;
}
/**
* Original VCF line (from file)
*/
public String getLine() {
return line;
}
public int getLineNum() {
return lineNum;
}
/**
* number of samples in this VCF file
*/
public int getNumberOfSamples() {
if (vcfFileIterator == null) return 0;
VcfHeader vh = vcfFileIterator.getVcfHeader();
if (vh == null) return 0;
return vh.getNumberOfSamples();
}
public double getQuality() {
return (quality != null ? quality : 0);
}
public String getRef() {
return ref;
}
public String getStr() {
return getChromosomeName() //
+ ":" + (start + 1) //
+ "_" + ref //
+ "/" + getAltsStr();
}
public List getVcfEffects() {
return getVcfEffects(null);
}
/**
* Parse 'EFF' info field and get a list of effects
*/
public synchronized List getVcfEffects(EffFormatVersion formatVersion) {
if (vcfEffects != null) return vcfEffects;
String effStr = null;
if (formatVersion == null) {
// Guess which INFO field could be
effStr = getInfo(EffFormatVersion.VCF_INFO_ANN_NAME);
if (effStr != null) {
formatVersion = EffFormatVersion.FORMAT_ANN; // Unspecied 'ANN' version
} else {
effStr = getInfo(EffFormatVersion.VCF_INFO_EFF_NAME);
if (effStr != null) formatVersion = EffFormatVersion.FORMAT_EFF; // Unspecied 'EFF' version
}
} else {
// Use corresponding INFO field
String effFieldName = VcfEffect.infoFieldName(formatVersion);
effStr = getInfo(effFieldName); // Get effect string from INFO field
}
// Create a list of effect
vcfEffects = new ArrayList<>();
// Note: An empty "EFF" string can be viewed as a FLAG type and transformed to a "true" value
if ((effStr == null) || effStr.isEmpty() || effStr.equals("true")) return vcfEffects;
// Add each effect
String effs[] = effStr.split(",");
for (String eff : effs) {
VcfEffect veff = new VcfEffect(eff, formatVersion); // Create and parse this effect
vcfEffects.add(veff);
}
return vcfEffects;
}
public VcfFileIterator getVcfFileIterator() {
return vcfFileIterator;
}
public VcfGenotype getVcfGenotype(int index) {
return getVcfGenotypes().get(index);
}
public List getVcfGenotypes() {
if (vcfGenotypes == null) parseGenotypes();
return vcfGenotypes;
}
/**
* Get VcfInfo type for a given ID
*/
public VcfHeaderInfo getVcfInfo(String id) {
return vcfFileIterator.getVcfHeader().getVcfHeaderInfo(id);
}
/**
* Get Info number for a given ID
*/
public VcfInfoType getVcfInfoNumber(String id) {
VcfHeaderInfo vcfInfo = vcfFileIterator.getVcfHeader().getVcfHeaderInfo(id);
if (vcfInfo == null) return null;
return vcfInfo.getVcfInfoType();
}
public boolean hasField(String filedName) {
return vcfFileIterator.getVcfHeader().getVcfHeaderInfo(filedName) != null;
}
public boolean hasGenotypes() {
return ((vcfGenotypes != null) && (vcfGenotypes.size() > 0)) || (genotypeFieldsStr != null);
}
public boolean hasInfo(String infoFieldName) {
if (info == null) parseInfo();
return info.containsKey(infoFieldName);
}
public boolean hasQuality() {
return quality != null;
}
/**
* Is this bi-allelic (based ONLY on the number of ALTs)
* WARINIG: You should use 'calcHetero()' method for a more precise calculation.
*/
public boolean isBiAllelic() {
if (alts == null) return false;
return alts.length == 1; // Only one ALT option? => homozygous
}
/**
* Do we have compressed genotypes in "HO,HE,NA" INFO fields?
*/
public boolean isCompressedGenotypes() {
return !hasGenotypes() && (getNumberOfSamples() > 0) && (hasInfo(VCF_INFO_HOMS) || hasInfo(VCF_INFO_HETS) || hasInfo(VCF_INFO_NAS));
}
public boolean isFilterPass() {
return filter.equals("PASS");
}
/**
* Is this multi-allelic (based ONLY on the number of ALTs)
* WARINIG: You should use 'calcHetero()' method for a more precise calculation.
*/
public boolean isMultiallelic() {
if (alts == null) return false;
return alts.length > 1; // More than one ALT option? => not homozygous
}
@Override
protected boolean isShowWarningIfParentDoesNotInclude() {
return false;
}
/**
* Is thins a VCF entry with a single SNP?
*/
public boolean isSingleSnp() {
return ref != null //
&& altStr != null //
&& ref.length() == 1 //
&& altStr.length() == 1 //
&& !ref.equalsIgnoreCase(altStr) //
;
}
/**
* Is this variant a singleton (appears only in one genotype)
*/
public boolean isSingleton() {
int count = 0;
for (VcfGenotype gen : this) {
if (gen.isVariant()) count++;
if (count > 1) return false;
}
return count == 1;
}
/**
* Is this a change or are the ALTs actually the same as the reference
*/
public boolean isVariant() {
if (alts == null || alts.length == 0) return false;
// Is any ALT is variant?
for (String alt : alts)
if (isVariant(alt)) return true;
return false;
}
/**
* Is this ALT string a variant?
*/
public boolean isVariant(String alt) {
return alt != null //
&& !alt.isEmpty() //
&& !alt.equals(VcfFileIterator.MISSING) // Missing ALT (".")?
&& !alt.equals(VCF_ALT_NON_REF) // '*'
&& !alt.equals(VCF_ALT_NON_REF_gVCF) // ''
&& !alt.equals(VCF_ALT_MISSING_REF) // '<*>'
&& !alt.equals(ref) // Is ALT different than REF?
;
}
@Override
public Iterator iterator() {
return getVcfGenotypes().iterator();
}
/**
* Calculate Minor allele count
*/
public int mac() {
long ac = -1;
// Do we have it annotated as AF or MAF?
if (hasField("MAC")) return (int) getInfoInt("MAC");
else if (hasField("AC")) ac = getInfoInt("AC");
// AC not found (or doesn't make sense)
if (ac <= 0) {
// We have to calculate
ac = 0;
for (byte genCode : getGenotypesScores())
if (genCode > 0) ac += genCode; // Don't count '-1' (i.e. missing genotypes)
}
// How many samples (alleles) do we have?
int numSamples = 0;
List sampleNames = vcfFileIterator.getVcfHeader().getSampleNames();
if (sampleNames != null) numSamples = sampleNames.size();
else numSamples = getVcfGenotypes().size();
// Always use the Minor Allele Count
if ((numSamples > 1) && (ac > numSamples)) ac = 2 * numSamples - ac;
return (int) ac;
}
/**
* Calculate Minor allele frequency
*/
public double maf() {
double maf = -1;
// Do we have it annotated as AF or MAF?
if (hasField("AF")) maf = getInfoFloat("AF");
else if (hasField("MAF")) maf = getInfoFloat("MAF");
else {
// No annotations, we have to calculate
int ac = 0, count = 0;
for (VcfGenotype gen : this) {
count += 2;
int genCode = gen.getGenotypeCode();
if (genCode > 0) ac += genCode;
}
maf = ((double) ac) / count;
}
// Always use the Minor Allele Frequency
if (maf > 0.5) maf = 1.0 - maf;
return maf;
}
/**
* Parse a 'line' from a 'vcfFileIterator'
*/
public void parse() {
// Parse line
String fields[] = line.split("\t", 10); // Only pare the fist 9 fields (i.e. do not parse genotypes)
// Is line OK?
if (fields.length >= 4) {
// Chromosome and position. VCF files are one-base, so inOffset should be 1.
chromosomeName = fields[0].trim();
// Chromosome
Chromosome chromo = vcfFileIterator.getChromosome(chromosomeName);
parent = chromo;
vcfFileIterator.sanityCheckChromo(chromosomeName, chromo); // Sanity check
// Start
start = vcfFileIterator.parsePosition(vcfFileIterator.readField(fields, 1));
// ID (e.g. might indicate dbSnp)
id = vcfFileIterator.readField(fields, 2);
// REF
ref = vcfFileIterator.readField(fields, 3).toUpperCase(); // Reference and change
strandMinus = false; // Strand is always positive (defined in VCF spec.)
// ALT
altStr = vcfFileIterator.readField(fields, 4).toUpperCase();
parseAlts(altStr);
// Quality
String qStr = vcfFileIterator.readField(fields, 5);
if (!qStr.isEmpty()) quality = Gpr.parseDoubleSafe(qStr);
else quality = null;
// Filter
filter = vcfFileIterator.readField(fields, 6); // Filter parameters
// INFO fields
infoStr = vcfFileIterator.readField(fields, 7);
info = null;
// Start & End coordinates are anchored to the reference genome, thus based on REF field (ALT is not taken into account)
parseEnd(altStr);
// Genotype format
format = null;
if (fields.length > 8) format = vcfFileIterator.readField(fields, 8); // This field is optional, So it can be null or EMPTY ('.')
// Add genotype fields (lazy parse)
if (fields.length > 9) genotypeFieldsStr = fields[9];
} else throw new RuntimeException("Impropper VCF entry: Not enough fields (missing tab separators?).\n" + line);
}
/**
* Parse ALT field
*/
void parseAlts(String altsStr) {
if (altsStr.length() == 1 || altsStr.indexOf(',') < 0) {
// SNP or single field (no commas)
alts = parseAltSingle(altsStr);
if (alts == null) alts = new String[0];
} else {
// Multiple fields (comma separated)
List altsList = new ArrayList<>();
// Parse each one
String altsSplit[] = altsStr.split(",");
for (String altSingle : altsSplit) {
String altsTmp[] = parseAltSingle(altSingle);
// Append all to list
if (altsTmp != null) {
for (String alt : altsTmp)
altsList.add(alt);
}
}
alts = altsList.toArray(EMPTY_STRING_ARRAY);
}
}
/**
* Parse single ALT record, return parsed ALTS
*/
String[] parseAltSingle(String altsStr) {
if (altsStr.length() != 1 // Not a SNP? Do not expand
|| !isVariant(altsStr) // Not a variant? Do not expand
|| !vcfFileIterator.isExpandIub() // Do not expand IUB option?
) {
String alts[] = { altsStr };
return alts;
}
// Not a variant?
if (altsStr.equals(VCF_ALT_NON_REF)) { return VCF_ALT_NON_REF_ARRAY; }
if (altsStr.equals(VCF_ALT_MISSING_REF)) { return VCF_ALT_MISSING_REF_ARRAY; }
if (altsStr.equals(VCF_ALT_NON_REF_gVCF)) { return VCF_ALT_NON_REF_gVCF_ARRAY; }
// SNP IUB conversion table
String alts[];
switch (altsStr) {
case "A":
case "C":
case "G":
case "T":
case "*":
case ".":
alts = new String[1];
alts[0] = altsStr;
break;
case "N": // aNy base
alts = new String[4];
alts[0] = "A";
alts[1] = "C";
alts[2] = "G";
alts[3] = "T";
break;
case "B": // B: not A
alts = new String[3];
alts[0] = "C";
alts[1] = "G";
alts[2] = "T";
break;
case "D": // D: not C
alts = new String[3];
alts[0] = "A";
alts[1] = "G";
alts[2] = "T";
break;
case "H": // H: not G
alts = new String[3];
alts[0] = "A";
alts[1] = "C";
alts[2] = "T";
break;
case "V": // V: not T
alts = new String[3];
alts[0] = "A";
alts[1] = "C";
alts[2] = "G";
break;
case "M":
alts = new String[2];
alts[0] = "A";
alts[1] = "C";
break;
case "R":
alts = new String[2];
alts[0] = "A";
alts[1] = "G";
break;
case "W": // Weak
alts = new String[2];
alts[0] = "A";
alts[1] = "T";
break;
case "S": // Strong
alts = new String[2];
alts[0] = "C";
alts[1] = "G";
break;
case "Y":
alts = new String[2];
alts[0] = "C";
alts[1] = "T";
break;
case "K":
alts = new String[2];
alts[0] = "G";
alts[1] = "T";
break;
default:
throw new RuntimeException("WARNING: Unkown IUB code for SNP '" + altsStr + "'");
}
return alts;
}
/**
* Parse 'end' coordinate
*/
void parseEnd(String altStr) {
end = start + ref.length() - 1;
// Imprecise variants are indicated by an angle brackets '<...>'
if (altStr.indexOf('<') >= 0) {
// If there is an 'END' tag, we should use it
if ((getInfo(VCF_INFO_END) != null)) {
// Get 'END' field and do some sanity check
end = (int) getInfoInt(VCF_INFO_END) - 1;
if (end < start) { throw new RuntimeException("INFO field 'END' is before varaint's 'POS'\n\tEND : " + end + "\n\tPOS : " + start); }
}
}
}
/**
* Parse GENOTPYE entries
*/
void parseGenotypes() {
if (isCompressedGenotypes()) {
uncompressGenotypes();
} else {
vcfGenotypes = new ArrayList<>();
// No genotype string? => Nothing to do
if (genotypeFieldsStr == null) return;
// Split genotypes and parse them
genotypeFields = genotypeFieldsStr.split("\t");
for (int i = 0; i < genotypeFields.length; i++) {
String gen = genotypeFields[i];
if (gen.equals(VcfFileIterator.MISSING)) gen = "";
addGenotype(gen);
}
}
}
/**
* Parse INFO fields
*/
void parseInfo() {
// Parse info entries
info = new HashMap<>();
for (String inf : infoStr.split(SUB_FIELD_SEP)) {
String vp[] = inf.split("=", 2);
if (vp.length > 1) info.put(vp[0], vp[1]); // Key = Value pair
else info.put(vp[0], "true"); // A property that is present, but has no value (e.g. "INDEL")
}
}
/**
* Parse LOF from VcfEntry
*/
public List parseLof() {
String lofStr = getInfo(LossOfFunction.VCF_INFO_LOF_NAME);
ArrayList lofList = new ArrayList<>();
if (lofStr == null || lofStr.isEmpty()) return lofList;
// Split comma separated list
String lofs[] = lofStr.split(",");
for (String lof : lofs)
lofList.add(new VcfLof(this, lof));
return lofList;
}
/**
* Parse NMD from VcfEntry
*/
public List parseNmd() {
String nmdStr = getInfo(LossOfFunction.VCF_INFO_NMD_NAME);
ArrayList nmdList = new ArrayList<>();
if (nmdStr == null || nmdStr.isEmpty()) return nmdList;
// Split comma separated list
String nmds[] = nmdStr.split(",");
for (String nmd : nmds)
nmdList.add(new VcfNmd(nmd));
return nmdList;
}
/**
* Parse genotype string (sparse matrix) and set all entries using 'value'
*/
void parseSparseGt(String str, byte gt[], int valueInt) {
if ((str == null) || (str.isEmpty()) || (str.equals("true"))) return;
// Split comma separated indeces
String idxs[] = str.split(",");
byte value = (byte) valueInt;
// Set all entries
for (String idx : idxs) {
int i = Gpr.parseIntSafe(idx);
gt[i] = value;
}
}
/**
* Remove INFO field
*/
public void removeInfo(String key) {
// Not in info field? => Nothing to do
if (!infoStr.contains(key)) return;
StringBuilder infoStrNew = new StringBuilder();
for (String infoEntry : infoStr.split(SUB_FIELD_SEP)) {
String keyValuePair[] = infoEntry.split("=", 2);
// Not the key we want to remove? => Add it
if (!keyValuePair[0].equals(key)) {
if (infoStrNew.length() > 0) infoStrNew.append(';');
infoStrNew.append(infoEntry);
}
}
// Create new string
infoStr = infoStrNew.toString();
// Update info hash
if (info != null) info.remove(key);
// Is this an 'EFF/ANN' field? Remove parsed effects
if (EffFormatVersion.isEffectVcfInfoField(key)) vcfEffects = null; // Reset field
}
/**
* Parse INFO fields
*/
public boolean rmInfo(String info) {
boolean deleted = false;
StringBuilder infoSb = new StringBuilder();
// Parse info entries
for (String inf : infoStr.split(SUB_FIELD_SEP)) {
String vp[] = inf.split("=");
if (vp[0].equals(info)) {
// Delete this field
deleted = true;
} else {
if (infoSb.length() > 0) infoSb.append(SUB_FIELD_SEP);
infoSb.append(vp[0]);
if (vp.length > 1) { // Flags don't need '=' sign
infoSb.append("=");
infoSb.append(vp[1]);
}
}
}
if (deleted) {
infoStr = infoSb.toString();
}
return deleted;
}
public void setFilter(String filter) {
this.filter = filter;
}
public void setFormat(String format) {
this.format = format;
}
public void setGenotypeStr(String genotypeFieldsStr) {
this.genotypeFieldsStr = genotypeFieldsStr;
}
public void setLineNum(int lineNum) {
this.lineNum = lineNum;
}
/**
* To string as a simple "CHR:START_REF/ALTs" format
*/
@Override
public String toStr() {
return getClass().getSimpleName() //
+ "_" + getChromosomeName() //
+ ":" + (start + 1) //
+ "_" + ref //
+ "/" + getAltsStr();
}
@Override
public String toString() {
boolean deleteLastTab = true;
StringBuilder sb = new StringBuilder(toStringNoGt());
sb.append("\t");
// Is there any 'format' field? It is optional, so it could be 'null'
if (format != null) {
sb.append((format.isEmpty() ? "." : format) + "\t");
// If we have vcfGenotypes parsed, use them
if ((vcfGenotypes != null) && !vcfGenotypes.isEmpty()) {
for (VcfGenotype vg : vcfGenotypes)
sb.append(vg + "\t");
} else if (genotypeFieldsStr != null) { // If vcfGenotypes have not been parsed, use raw fields
sb.append(genotypeFieldsStr);
deleteLastTab = false;
}
}
if (deleteLastTab) sb.deleteCharAt(sb.length() - 1); // Delete last tab
return sb.toString();
}
/**
* Show only first eight fields (no genotype entries)
*/
public String toStringNoGt() {
// Use original chromosome name or named from chromosome object
String chr = null;
if (chromosomeName != null) chr = chromosomeName;
else if ((parent != null) && (parent instanceof Chromosome)) chr = parent.getId();
else if (parent != null) chr = getChromosomeName();
else chr = ".";
StringBuilder sb = new StringBuilder(chr //
+ "\t" + (start + 1) //
+ "\t" + (id.isEmpty() ? "." : id) //
);
// REF and ALT
String refStr = (ref == null || ref.isEmpty() ? "." : ref);
sb.append("\t" + refStr);
sb.append("\t" + getAltsStr());
// Quality, filter, info, format...
sb.append("\t" + (quality != null ? quality + "" : "."));
sb.append("\t" + ((filter == null) || filter.isEmpty() ? "." : filter));
sb.append("\t" + ((infoStr == null) || infoStr.isEmpty() ? "." : infoStr));
return sb.toString();
}
/**
* Uncompress VCF entry having genotypes in "HO,HE,NA" fields
*/
public VcfEntry uncompressGenotypes() {
// Not compressed? Nothing to do
if (!isCompressedGenotypes()) return this;
// Get 'sparse' matrix entries
String hoStr = getInfo(VCF_INFO_HOMS);
String heStr = getInfo(VCF_INFO_HETS);
String naStr = getInfo(VCF_INFO_NAS);
// Parse 'sparse' entries
List sampleNames = getVcfFileIterator().getVcfHeader().getSampleNames();
if (sampleNames == null) throw new RuntimeException("Cannot find sample names in VCF header. Unable to uncompress genotypes.");
int numSamples = sampleNames.size();
byte gt[] = new byte[numSamples];
parseSparseGt(naStr, gt, -1);
parseSparseGt(heStr, gt, 1);
parseSparseGt(hoStr, gt, 2);
// Remove info fields
if (hoStr != null) rmInfo(VCF_INFO_HOMS);
if (heStr != null) rmInfo(VCF_INFO_HETS);
if (naStr != null) rmInfo(VCF_INFO_NAS);
setFormat("GT");
// Create output string
for (int i = 0; i < gt.length; i++) {
String gtStr;
switch (gt[i]) {
case -1:
gtStr = "./.";
break;
case 0:
gtStr = "0/0";
break;
case 1:
gtStr = "0/1";
break;
case 2:
gtStr = "1/1";
break;
default:
throw new RuntimeException("Unknown code '" + gt[i] + "'");
}
addGenotype(gtStr);
}
return this;
}
/**
* Create a list of variants from this VcfEntry
*/
public List variants() {
if (variants != null) return variants;
// Create list of variants
variants = new LinkedList<>();
// Create one Variant for each ALT
Chromosome chr = (Chromosome) parent;
if (!isVariant()) {
// Not a variant?
List vars = variants(chr, start, ref, null, id);
String alt = ".";
// Add original 'ALT' field as genotype
for (Variant variant : vars)
variant.setGenotype(alt);
variants.addAll(vars);
} else {
// At least one variant
for (String alt : alts) {
if (!isVariant(alt)) alt = null;
List vars = variants(chr, start, ref, alt, id);
variants.addAll(vars);
}
}
return variants;
}
/**
* Create a variant
*/
List variants(Chromosome chromo, int start, String reference, String alt, String id) {
List list = null;
if (alt != null) alt = alt.toUpperCase();
if (alt == null || alt.isEmpty() || alt.equals(reference)) {
// Non-variant
list = Variant.factory(chromo, start, reference, null, id, false);
} else if (alt.charAt(0) == '<') {
// Structural variants
if (alt.startsWith(" 6 PASS IMPRECISE;SVTYPE=DEL;END=321887;SVLEN=-105;CIPOS=-56,20;CIEND=-10,62
String ch = ref;
int startNew = start;
if (end > start) {
startNew = start + reference.length();
int size = end - startNew + 1;
char change[] = new char[size];
for (int i = 0; i < change.length; i++)
change[i] = reference.length() > i ? reference.charAt(i) : 'N';
ch = new String(change);
}
list = Variant.factory(chromo, startNew, ch, "", id, false);
} else if (alt.startsWith("();
list.add(var);
} else if (alt.startsWith("();
list.add(var);
}
} else if ((alt.indexOf('[') >= 0) || (alt.indexOf(']') >= 0)) {
// Translocations
// Parse ALT string
boolean left = alt.indexOf(']') >= 0;
String sep = (left ? "\\]" : "\\[");
String tpos[] = alt.split(sep);
String pos = tpos[1];
boolean before = (alt.indexOf(']') == 0) || (alt.indexOf('[') == 0);
String altBases = (before ? tpos[2] : tpos[0]);
// Parse 'chr:start'
String posSplit[] = pos.split(":");
String trChrName = posSplit[0];
Chromosome trChr = chromo.getGenome().getOrCreateChromosome(trChrName);
int trStart = Gpr.parseIntSafe(posSplit[1]) - 1;
VariantBnd var = new VariantBnd(chromo, start, ref, altBases, trChr, trStart, left, before);
list = new LinkedList<>();
list.add(var);
} else if (reference.length() == alt.length()) {
// Case: SNP, MNP
if (reference.length() == 1) {
// SNPs
// 20 3 . C G . PASS DP=100
list = Variant.factory(chromo, start, reference, alt, id, vcfFileIterator.isExpandIub());
} else {
// MNPs
// 20 3 . TC AT . PASS DP=100
// Sometimes the first bases are the same and we can trim them
int startDiff = Integer.MAX_VALUE;
for (int i = 0; i < reference.length(); i++)
if (reference.charAt(i) != alt.charAt(i)) startDiff = Math.min(startDiff, i);
// MNPs
// Sometimes the last bases are the same and we can trim them
int endDiff = 0;
for (int i = reference.length() - 1; i >= 0; i--)
if (reference.charAt(i) != alt.charAt(i)) endDiff = Math.max(endDiff, i);
String newRef = reference.substring(startDiff, endDiff + 1);
String newAlt = alt.substring(startDiff, endDiff + 1);
list = Variant.factory(chromo, start + startDiff, newRef, newAlt, id, vcfFileIterator.isExpandIub());
}
} else {
// Short Insertions, Deletions or Mixed Variants (substitutions)
VcfRefAltAlign align = new VcfRefAltAlign(alt, reference);
align.align();
int startDiff = align.getOffset();
switch (align.getVariantType()) {
case DEL:
// Case: Deletion
// 20 2 . TC T . PASS DP=100
// 20 2 . AGAC AAC . PASS DP=100
String ref = "";
String ch = align.getAlignment();
if (!ch.startsWith("-")) throw new RuntimeException("Deletion '" + ch + "' does not start with '-'. This should never happen!");
list = Variant.factory(chromo, start + startDiff, ref, ch, id, vcfFileIterator.isExpandIub());
break;
case INS:
// Case: Insertion of A { tC ; tCA } tC is the reference allele
// 20 2 . TC TCA . PASS DP=100
ch = align.getAlignment();
ref = "";
if (!ch.startsWith("+")) throw new RuntimeException("Insertion '" + ch + "' does not start with '+'. This should never happen!");
list = Variant.factory(chromo, start + startDiff, ref, ch, id, vcfFileIterator.isExpandIub());
break;
case MIXED:
// Case: Mixed variant (substitution)
reference = reference.substring(startDiff);
alt = alt.substring(startDiff);
list = Variant.factory(chromo, start + startDiff, reference, alt, id, vcfFileIterator.isExpandIub());
break;
default:
// Other change type?
throw new RuntimeException("Unsupported VCF change type '" + align.getVariantType() + "'\n\tRef: " + reference + "'\n\tAlt: '" + alt + "'\n\tVcfEntry: " + this);
}
}
//---
// Add original 'ALT' field as genotype
//---
if (list == null) list = new LinkedList<>();
for (Variant variant : list)
variant.setGenotype(alt);
return list;
}
}
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