fix: DBS across codon boundary correctly classified as nonsense (#84)#96
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jmg421 wants to merge 3 commits into
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fix: DBS across codon boundary correctly classified as nonsense (#84)#96jmg421 wants to merge 3 commits into
jmg421 wants to merge 3 commits into
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Bioconductor#81) Large INDELs (e.g. 2542bp deletions) that span multiple exons were silently dropped by locateVariants() and predictCoding() because the internal call to mapToTranscripts() uses type='within', which requires the variant to fit entirely within a single exon/CDS element. Changes: - locateVariants (.makeResult): after mapToTranscripts, detect variants that overlap the transcript (type='any') but were not mapped. These are now included in results with LOCATION='coding' and LOCSTART/LOCEND set to NA. A warning is emitted identifying the rescued variants. - predictCoding (.localCoordinates): emit a warning when variants overlap CDS regions but cannot be mapped to transcript coordinates, directing users to locateVariants() for identification. This is the minimal fix that prevents silent data loss. Full amino acid consequence prediction for multi-exon spanning variants would require changes to GenomicFeatures::mapToTranscripts itself. Fixes Bioconductor#81
expand() on a CollapsedVCF was calling mcols(rdexp) <- NULL after expanding rowRanges, which wiped all user-added metadata columns (e.g. SNP_name, num_alts). The fast path (no multi-allelic sites) already preserved these columns correctly. Fix: simply expand rd[idx, ] without wiping mcols. The VCF() constructor accepts rowRanges with extra mcols — they are stored in the rowRanges slot alongside paramRangeID, separate from the fixed fields (REF/ALT/QUAL/FILTER). Fixes Bioconductor#85
…onductor#84) A dinucleotide base substitution (DBS) spanning a codon boundary that produces a stop codon in one of the two affected amino acids (e.g. VARAA='P*') was misclassified as 'nonsynonymous' instead of 'nonsense'. Root cause: the nonsense check used `as.character(varAA) %in% "*"` which only matches when the entire VARAA string is '*'. For multi-codon DBS, VARAA is multi-character (e.g. 'P*') and the check fails. Fix: use `grepl("*", ..., fixed=TRUE)` to detect stop codons anywhere in the translated variant amino acid sequence. Any premature stop truncates the protein regardless of flanking residues. Fixes Bioconductor#84
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Summary
A dinucleotide base substitution (DBS) that spans a codon boundary and produces a stop codon in one of the two resulting amino acids was misclassified as
nonsynonymousinstead ofnonsense.Example from the issue:
GG→AAon the - strand producesVARAA='P*'(proline + stop), but was reported as nonsynonymous because the check only matched when VARAA was exactly'*'.Root Cause
Line 184 of
methods-predictCoding.R:%in% "*"requires the entire string to equal*. For a DBS spanning two codons,varAAis two characters (e.g.P*), so the check fails.Fix
grepldetects a stop codon anywhere in the translated variant sequence. Any premature stop truncates the protein — it doesn't matter what precedes it.Testing
Added
test_predictCoding_dbs_nonsenseverifying that:P*→ nonsense (stop after one residue)*→ nonsense (classic single-codon stop)PQ→ nonsynonymous (no stop)*L→ nonsense (stop at first position)Fixes #84