public static IList <IAnnotatedTranscript> GetAnnotatedTranscripts(IVariant variant,
ITranscript[] transcriptCandidates, ISequence compressedSequence, IPredictionCache siftCache,
IPredictionCache polyphenCache, ITranscript[] geneFusionCandidates = null)
{
var annotatedTranscripts = new List <IAnnotatedTranscript>();
foreach (var transcript in transcriptCandidates)
{
if (transcript.Id.IsPredictedTranscript())
{
continue;
}
var annotationStatus = DecideAnnotationStatus(variant, transcript, variant.Behavior);
var annotatedTranscript = GetAnnotatedTranscript(variant, compressedSequence, transcript,
annotationStatus, siftCache, polyphenCache, geneFusionCandidates);
if (annotatedTranscript != null)
{
annotatedTranscripts.Add(annotatedTranscript);
}
}
return(annotatedTranscripts);
}
public static void GetAnnotatedTranscripts(IVariant variant, ITranscript[] transcriptCandidates,
ISequence compressedSequence, IList <IAnnotatedTranscript> annotatedTranscripts,
ISet <string> overlappingGenes, IList <IOverlappingTranscript> overlappingTranscripts,
IPredictionCache siftCache, IPredictionCache polyphenCache,
ITranscript[] geneFusionCandidates = null)
{
foreach (var transcript in transcriptCandidates)
{
var annotationStatus = DecideAnnotationStatus(variant, transcript, variant.Behavior, transcript.Gene);
if (annotationStatus != Status.NoAnnotation && variant.Behavior.ReportOverlappingGenes)
{
overlappingGenes.Add(transcript.Gene.Symbol);
}
if (variant.Behavior.NeedVerboseTranscripts)
{
AddOverlappingTranscript(annotationStatus, transcript, variant, overlappingTranscripts);
}
var annotatedTranscript = GetAnnotatedTranscript(variant, compressedSequence, transcript,
annotationStatus, siftCache, polyphenCache, geneFusionCandidates);
if (annotatedTranscript != null)
{
annotatedTranscripts.Add(annotatedTranscript);
}
}
}
private static PredictionScore GetPredictionScore(int proteinPosition, char newAminoAcid,
IPredictionCache predictionCache, int predictionIndex)
{
return(predictionIndex == -1
? null
: predictionCache?.GetProteinFunctionPrediction(predictionIndex, newAminoAcid, proteinPosition));
}
private void LoadPredictionCaches(ushort refIndex)
{
if (refIndex == _currentRefIndex)
{
return;
}
if (refIndex == ushort.MaxValue)
{
ClearCache();
return;
}
_siftCache = _siftReader.Read(refIndex);
_polyphenCache = _polyphenReader.Read(refIndex);
_currentRefIndex = refIndex;
}
public static IList <IAnnotatedTranscript> GetAnnotatedTranscripts(IVariant variant,
ITranscript[] transcriptCandidates, ISequence compressedSequence, IPredictionCache siftCache,
IPredictionCache polyphenCache)
{
var annotatedTranscripts = new List <IAnnotatedTranscript>();
foreach (var transcript in transcriptCandidates)
{
var annotationStatus = DecideAnnotationStatus(variant, transcript, variant.Behavior,
variant.Chromosome.FlankingLength);
var annotatedTranscript = GetAnnotatedTranscript(variant, compressedSequence, transcript,
annotationStatus, siftCache, polyphenCache);
if (annotatedTranscript != null)
{
annotatedTranscripts.Add(annotatedTranscript);
}
}
return(annotatedTranscripts);
}
private static IAnnotatedTranscript GetAnnotatedTranscript(IVariant variant, ISequence compressedSequence,
ITranscript transcript, Status annotationStatus, IPredictionCache siftCache, IPredictionCache polyphenCache,
ITranscript[] geneFusionCandidates)
{
IAnnotatedTranscript annotatedTranscript = null;
// ReSharper disable once SwitchStatementMissingSomeCases
switch (annotationStatus)
{
case Status.FlankingAnnotation:
annotatedTranscript =
FlankingTranscriptAnnotator.GetAnnotatedTranscript(variant.End, transcript);
break;
case Status.ReducedAnnotation:
annotatedTranscript = ReducedTranscriptAnnotator.GetAnnotatedTranscript(transcript, variant, geneFusionCandidates);
break;
case Status.CompleteOverlapAnnotation:
annotatedTranscript = ReducedTranscriptAnnotator.GetCompleteOverlapTranscript(transcript);
break;
case Status.RohAnnotation:
annotatedTranscript = RohTranscriptAnnotator.GetAnnotatedTranscript(transcript);
break;
case Status.FullAnnotation:
var acidsProvider = variant.Chromosome.UcscName == "chrM"
? MitoAminoAcidsProvider
: AminoAcidsProvider;
annotatedTranscript = FullTranscriptAnnotator.GetAnnotatedTranscript(transcript, variant,
compressedSequence, siftCache, polyphenCache, acidsProvider);
break;
}
return(annotatedTranscript);
}
private static (PredictionScore Sift, PredictionScore PolyPhen) GetPredictionScores(IMappedPosition position,
string refAminoAcid, string altAminoAcid, IPredictionCache siftCache, IPredictionCache polyphenCache,
int siftIndex, int polyphenIndex)
{
if (!NeedPredictionScore(position.ProteinStart, position.ProteinEnd, refAminoAcid, altAminoAcid) ||
position.ProteinStart == -1)
{
return(null, null);
}
var newAminoAcid = altAminoAcid[0];
var siftScore = GetPredictionScore(position.ProteinStart, newAminoAcid, siftCache, siftIndex);
var polyphenScore = GetPredictionScore(position.ProteinStart, newAminoAcid, polyphenCache, polyphenIndex);
return(siftScore, polyphenScore);
}
public static IAnnotatedTranscript GetAnnotatedTranscript(ITranscript transcript, IVariant leftShiftedVariant,
ISequence refSequence, IPredictionCache siftCache, IPredictionCache polyphenCache, AminoAcids aminoAcids)
{
var rightShiftedVariant = VariantRotator.Right(leftShiftedVariant, transcript, refSequence,
transcript.Gene.OnReverseStrand);
var leftAnnotation = AnnotateTranscript(transcript, leftShiftedVariant, aminoAcids, refSequence);
var rightAnnotation = ReferenceEquals(leftShiftedVariant, rightShiftedVariant)
? leftAnnotation
: AnnotateTranscript(transcript, rightShiftedVariant, aminoAcids, refSequence);
var consequences = GetConsequences(transcript, leftShiftedVariant, leftAnnotation.VariantEffect);
var hgvsCoding = HgvsCodingNomenclature.GetHgvscAnnotation(transcript, rightShiftedVariant, refSequence,
rightAnnotation.Position.RegionStartIndex, rightAnnotation.Position.RegionEndIndex);
var hgvsProtein = HgvsProteinNomenclature.GetHgvsProteinAnnotation(transcript,
rightAnnotation.RefAminoAcids, rightAnnotation.AltAminoAcids, rightAnnotation.TranscriptAltAllele,
rightAnnotation.Position, rightAnnotation.VariantEffect, rightShiftedVariant, refSequence, hgvsCoding,
leftShiftedVariant.Chromosome.UcscName == "chrM");
var predictionScores = GetPredictionScores(leftAnnotation.Position, leftAnnotation.RefAminoAcids,
leftAnnotation.AltAminoAcids, siftCache, polyphenCache, transcript.SiftIndex, transcript.PolyPhenIndex);
return(new AnnotatedTranscript(transcript, leftAnnotation.RefAminoAcids, leftAnnotation.AltAminoAcids,
leftAnnotation.RefCodons, leftAnnotation.AltCodons, leftAnnotation.Position, hgvsCoding, hgvsProtein,
predictionScores.Sift, predictionScores.PolyPhen, consequences, false));
}
private void ClearCache()
{
_siftCache = null;
_polyphenCache = null;
_currentRefIndex = ushort.MaxValue;
}
