/**
* Is this single change a LOF?
*
* <p>Criteria: 1) Core splice sites acceptors or donors (only CORE ones) 2) Stop gained (if this
* happens at the last part of the protein, we assume it has no effect) 3) Frame shifts
*
* @param changeEffect
* @return
*/
protected boolean isNmd(ChangeEffect changeEffect) {
Transcript tr = changeEffect.getTranscript();
if (tr == null)
throw new RuntimeException("Transcript not found for change:\n\t" + changeEffect);
// Only one exon? Nothing to do (there is no exon-exon junction)
if (tr.numChilds() <= 1) return false;
// Find last valid NMD position
int lastNmdPos = lastNmdPos(tr);
if (lastNmdPos < 0) return false; // No valid 'lastNmdPos'? => There is no NMD event.
// Does this change affect the region 'before' this last NMD position? => It is assumed to be
// NMD
Variant seqChange = changeEffect.getSeqChange();
boolean nmd;
if (tr.isStrandPlus()) nmd = seqChange.getStart() <= lastNmdPos;
else nmd = lastNmdPos <= seqChange.getEnd();
// Update sets and counters
if (nmd) {
transcriptsNmd.add(
changeEffect
.getTranscript()); // Unique transcripts affected (WARNING: null will be added)
genesNmd.add(changeEffect.getGene()); // Unique genes affected (WARNING: null will be added)
nmdCount++;
}
return nmd;
}
/**
* Is this single change a LOF?
*
* <p>Criteria: 1) Core splice sites acceptors or donors (only CORE ones) 2) Stop gained (if this
* happens at the last part of the protein, we assume it has no effect) 3) Frame shifts
*
* @param changeEffect
* @return
*/
protected boolean isLof(ChangeEffect changeEffect) {
// Not a sequence change? => Not LOF
if ((changeEffect.getSeqChange() != null) && (!changeEffect.getSeqChange().isVariant()))
return false;
// Is this change affecting a protein coding gene?
Gene gene = changeEffect.getGene();
Transcript tr = changeEffect.getTranscript();
if ((gene == null) // No gene affected?
|| (tr == null) // No transcript affected?
|| (!gene.isProteinCoding()
&& !config.isTreatAllAsProteinCoding()) // Not a protein coding gene?
|| (!tr.isProteinCoding()
&& !config.isTreatAllAsProteinCoding()) // Not a protein coding transcript?
) return false;
// ---
// Is this variant a LOF?
// ---
boolean lof = false;
// Frame shifts
if (changeEffect.getEffectType() == EffectType.FRAME_SHIFT) {
// It is assumed that even with a protein coding change at the last 5% of the protein, the
// protein could still be functional.
double perc = percentCds(changeEffect);
lof |= (ignoreProteinCodingBefore <= perc) && (perc <= ignoreProteinCodingAfter);
}
// Deletion? Is another method to check
if (changeEffect.getSeqChange().isDel()) lof |= isLofDeletion(changeEffect);
// The following effect types can be considered LOF
switch (changeEffect.getEffectType()) {
case SPLICE_SITE_ACCEPTOR:
case SPLICE_SITE_DONOR:
// Core splice sites are considered LOF
if ((changeEffect.getMarker() != null)
&& (changeEffect.getMarker() instanceof SpliceSite)) {
// Get splice site marker and check if it is 'core'
SpliceSite spliceSite = (SpliceSite) changeEffect.getMarker();
if (spliceSite.intersectsCoreSpliceSite(changeEffect.getSeqChange()))
lof = true; // Does it intersect the CORE splice site?
}
break;
case STOP_GAINED:
lof |= isNmd(changeEffect);
break;
case RARE_AMINO_ACID:
case START_LOST:
// This one is not in the referenced papers, but we assume that RARE AA and START_LOSS
// changes are damaging.
lof = true;
break;
default: // All others are not considered LOF
break;
}
// Update sets
if (lof) {
transcriptsLof.add(
changeEffect
.getTranscript()); // Unique transcripts affected (WARNING: null will be added)
genesLof.add(changeEffect.getGene()); // Unique genes affected (WARNING: null will be added)
}
return lof;
}
