Enhancing Variant Interpretation at the UK NEQAS UV Participants Meeting 2013
The UK NEQAS UV Participants Meeting 2013 focused on advancing the quality and interpretation of genetic variants. Key discussions included the implementation of advanced visualization tools for over 18,000 human protein-coding genes, as well as methods for managing and reporting variants in compliance with HGVS nomenclature. The meeting also explored critical judgment exercises, splicing predictions, and the integration of prediction tools for missense and splicing variants. A strong emphasis was placed on data accuracy and the use of reliable databases, ensuring improved variant classification and reporting processes.
Enhancing Variant Interpretation at the UK NEQAS UV Participants Meeting 2013
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Presentation Transcript
in a quality perspective UK NEQAS UV Participants Meeting 2013
Alamut • Gene browser over 18,000+ human protein-coding genes • Advanced visualization of gene-related annotations • Integration of prediction tools • Variant management and reporting • HGVS nomenclature compliancy UK NEQAS UV Participants Meeting 2013
Alamut Ref. Genome Conservation Ref. transcripts dbSNP variations ESP variations HGMD mutations Proteindomains Orthologues UK NEQAS UV Participants Meeting 2013
Data Sources dbSNP NHLBI GO ESP RefSeq InterPro -Genome -Transcripts Domains Variants LSDBs +Orthologues Conservation Genes HUGO -Proteins -Missense variants Mutations Alamut Database Abstracts UK NEQAS UV Participants Meeting 2013
MissensePredictions UK NEQAS UV Participants Meeting 2013
SplicingPredictions UK NEQAS UV Participants Meeting 2013
ExerciseCriticalJudgment! • Software = Program code + Data UK NEQAS UV Participants Meeting 2013
ExerciseCriticalJudgment! • Software = Program code + bugs + Data + errors UK NEQAS UV Participants Meeting 2013
ExerciseCriticalJudgment! • Software = Program code + bugs + Data + errors UK NEQAS UV Participants Meeting 2013
Data • dbSNP is not a database of polymorphisms • Conservation scores depend on sequences and alignment algorithms • Transcripts can be misplaced (very unusual) • Protein domains are mostly predicted • Orthologues are mostly computed UK NEQAS UV Participants Meeting 2013
MissensePredictions • WhyAlign GVGD, PolyPhen-2, SIFT, MutationTaster? • Reputation • Automatability • Right to use in commercial software • Complexalgorithmsbased on AA physico-chemicalproperties, AA conservation, protein structure, and more • Predictions ±stronglydepend on Alamut-suppliedorthologuealignment UK NEQAS UV Participants Meeting 2013
SplicingPredictions • Why SSF, MaxEnt, NNSPLICE, GeneSplicer, HSF? • ditto • Simple algorithms based on sequence • MaxEnt often considered as the most accurate • (Splicing regulation predictions: for experts only!) UK NEQAS UV Participants Meeting 2013
Quality Contribution • Up-to-date data • Visual feedback • HGVS nomenclature (when in doubt check with Mutalyzer) • Manually-curated orthologue alignments • NGS alignment and coverage visualization UK NEQAS UV Participants Meeting 2013
NGS AlignmentViewer UK NEQAS UV Participants Meeting 2013
Alamut / CMGS-VKGL Guidelines • 3.3 Variant Nomenclature • 3.4 Variant Submission • 4.1 LSDBs • 4.2 SNP Databases • 4.7 Species Conservation • 4.8 MissensePredictions • 4.9 Splice Site Predictions • 4.14 InterpretationProcessStandardization • 5.1 ReportingVariants • 5.4 Variant Classification UK NEQAS UV Participants Meeting 2013
34 labs UK NEQAS UV Participants Meeting 2013
