protected CodonChange(Variant variant, Transcript transcript, VariantEffects variantEffects)
{
Transcript = transcript;
VariantEffects = variantEffects;
Variant = variant;
}
/// <summary>
/// Calculate the effect on an exon
/// </summary>
/// <param name="exon"></param>
/// <returns></returns>
protected virtual bool ChangeCodon(Exon exon)
{
throw new InvalidOperationException("Unimplemented method codonChangeSingle() for\n\t\tVariant type : " + Variant.GetType().Name + "\n\t\tClass : " + GetType().Name + "\n\t\tVariant : " + Variant);
}
/// <summary>
/// Check that the base in the exon corresponds with the one in the SNP
/// </summary>
/// <param name="variant"></param>
/// <returns></returns>
public ErrorWarningType SanityCheck(Variant variant)
{
if (!Intersects(variant))
{
return(ErrorWarningType.NONE);
}
// Only makes sense for SNPs and MNPs
if ((variant.VarType != Variant.VariantType.SNV) && (variant.VarType != Variant.VariantType.MNV))
{
return(ErrorWarningType.NONE);
}
// Calculate reference sequence coordinates
long mstart = Math.Max(variant.OneBasedStart, OneBasedStart);
long idxStart = mstart - OneBasedStart;
if (Sequence.Count <= 0)
{
return(ErrorWarningType.WARNING_SEQUENCE_NOT_AVAILABLE);
}
if (idxStart >= Sequence.Count)
{
return(ErrorWarningType.ERROR_OUT_OF_EXON);
}
long mend = Math.Min(variant.OneBasedEnd, OneBasedEnd);
long len = mend - mstart + 1;
ISequence realReference = basesAt(idxStart, len);
// Get variant's reference coordinates
long varRefStart = mstart - variant.OneBasedStart;
if (varRefStart < 0)
{
return(ErrorWarningType.ERROR_OUT_OF_EXON);
}
long varRefEnd = mend - variant.OneBasedStart;
// Variant's reference sequence
string refStr;
//if (variant.isNonRef()) // used for some advanced stuff in SnpEff, comparing cancer vs somatic tissue
//{
// refStr = ((VariantNonRef)variant).getVariantRef().getAlt();
//}
//else
//{
refStr = variant.ReferenceAlleleString;
//}
if (varRefEnd >= refStr.Length)
{
return(ErrorWarningType.ERROR_OUT_OF_EXON);
}
int varRefLen = (int)(varRefEnd - varRefStart + 1);
string variantReference = refStr.Substring((int)varRefStart, varRefLen);
// Reference sequence different than expected?
if (!realReference.Equals(variantReference))
{ //
return(ErrorWarningType.WARNING_REF_DOES_NOT_MATCH_GENOME);
}
// OK
return(ErrorWarningType.NONE);
}
/// <summary>
/// Calculate additional effect due to codon changes, e.g. A frame-shift that also affects a stop codon
/// </summary>
/// <param name="codonsOld"></param>
/// <param name="codonsNew"></param>
/// <param name="codonNum"></param>
/// <param name="codonIndex"></param>
/// <returns></returns>
protected EffectType AdditionalEffect(string codonsOld, string codonsNew, int codonNum, int codonIndex)
{
EffectType newEffectType = EffectType.NONE;
bool hasOldAa = CodonExtensions.TryTranslateCodon(Transcript.Gene.Chromosome.Mitochondrial, codonsOld, out byte oldAA);
bool hasNewAa = CodonExtensions.TryTranslateCodon(Transcript.Gene.Chromosome.Mitochondrial, codonsNew, out byte newAA);
bool isStartNew = Transcript.Gene.Chromosome.Mitochondrial ?
CodonsVertebrateMitochondrial.START_CODONS.Contains(codonsNew.ToUpper(CultureInfo.InvariantCulture)) :
CodonsStandard.START_CODONS.Contains(codonsNew.ToUpper(CultureInfo.InvariantCulture));
bool isStartOld = Transcript.Gene.Chromosome.Mitochondrial ?
CodonsVertebrateMitochondrial.START_CODONS.Contains(codonsOld.ToUpper(CultureInfo.InvariantCulture)) :
CodonsStandard.START_CODONS.Contains(codonsOld.ToUpper(CultureInfo.InvariantCulture));
bool isStopOld = hasOldAa && oldAA == Alphabets.Protein.Ter;
bool isStopNew = hasNewAa && newAA == Alphabets.Protein.Ter;
if (Variant.isSnv() || Variant.isMnv())
{
// SNM and MNP effects
if (oldAA.Equals(newAA))
{
// Same AA: Synonymous coding
if (codonNum == 0 && isStartOld)
{
// It is in the first codon (which also is a start codon)
if (isStartNew)
{
newEffectType = EffectType.SYNONYMOUS_START;
} // The new codon is also a start codon => SYNONYMOUS_START
else
{
newEffectType = EffectType.START_LOST;
} // The AA is the same, but the codon is not a start codon => start lost
}
else if (isStopOld)
{
// Stop codon
if (isStopNew)
{
newEffectType = EffectType.SYNONYMOUS_STOP;
} // New codon is also a stop => SYNONYMOUS_STOP
else
{
newEffectType = EffectType.STOP_LOST;
} // New codon is not a stop, the we've lost a stop
}
else
{
newEffectType = EffectType.SYNONYMOUS_CODING; // All other cases are just SYNONYMOUS_CODING
}
}
else
{
// Different AA: Non-synonymous coding
if ((codonNum == 0) && isStartOld)
{
// It is in the first codon (which also is a start codon)
if (isStartNew)
{
newEffectType = EffectType.NON_SYNONYMOUS_START;
} // Non-synonymous mutation on first codon => start lost
else
{
newEffectType = EffectType.START_LOST;
} // Non-synonymous mutation on first codon => start lost
}
else if (isStopOld)
{
// Stop codon
if (isStopNew)
{
newEffectType = EffectType.NON_SYNONYMOUS_STOP;
} // Notice: This should never happen for SNPs! (for some reason I removed this comment at some point and that create some confusion): http://www.biostars.org/post/show/51352/in-snpeff-impact-what-is-difference-between-stop_gained-and-non-synonymous_stop/
else
{
newEffectType = EffectType.STOP_LOST;
}
}
else if (isStopNew)
{
newEffectType = EffectType.STOP_GAINED;
}
else
{
newEffectType = EffectType.NON_SYNONYMOUS_CODING; // All other cases are just NON_SYN
}
}
}
else
{
// Add a new effect in some cases
if ((codonNum == 0) && isStartOld && !isStartNew)
{
newEffectType = EffectType.START_LOST;
}
else if (isStopOld && !isStopNew)
{
newEffectType = EffectType.STOP_LOST;
}
else if (!isStopOld && isStopNew)
{
newEffectType = EffectType.STOP_GAINED;
}
}
return(newEffectType);
}
/// <summary>
/// Apply a variant to this exon interval and sequence
/// </summary>
/// <param name="variant"></param>
/// <returns></returns>
public override Interval ApplyVariant(Variant variant)
{
IntervalSequence i = base.ApplyVariant(variant) as IntervalSequence;
return(new Exon(i.Parent as Transcript, i.Sequence, i.Source, i.OneBasedStart, i.OneBasedEnd, i.ChromosomeID, i.Strand, i.Variants, FeatureMetadata));
}