1. 01/03/2013UK NEQAS UV Participants Meeting 2013 in a quality perspective

2. 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 01/03/2013UK NEQAS UV Participants Meeting 20132

3. Alamut 01/03/2013UK NEQAS UV Participants Meeting 20133 Ref. Genome Conservation Ref. transcripts dbSNP variations ESP variations HGMD mutations Protein domains Orthologues

4. Data Sources 01/03/2013UK NEQAS UV Participants Meeting 2013 Alamut Database RefSeq dbSNP -Genome -Transcripts HUGO InterPro Domains Variants Genes -Proteins -Missense variants +Orthologues LSDBs Abstracts Conservation Mutations 4 NHLBI GO ESP

5. Missense Predictions 01/03/2013UK NEQAS UV Participants Meeting 20135

6. Splicing Predictions 01/03/2013UK NEQAS UV Participants Meeting 20136

7. Exercise Critical Judgment! Software = Program code + Data 01/03/2013UK NEQAS UV Participants Meeting 20137

8. Exercise Critical Judgment! Software = Program code + bugs + Data + errors 01/03/2013UK NEQAS UV Participants Meeting 20138

9. Exercise Critical Judgment! Software = Program code + bugs + Data + errors 01/03/2013UK NEQAS UV Participants Meeting 20139

10. 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 01/03/2013UK NEQAS UV Participants Meeting 201310

11. Missense Predictions Why Align GVGD, PolyPhen-2, SIFT, MutationTaster? – Reputation – Automatability – Right to use in commercial software Complex algorithms based on AA physico-chemical properties, AA conservation, protein structure, and more Predictions ±strongly depend on Alamut-supplied orthologue alignment 01/03/2013UK NEQAS UV Participants Meeting 201311

12. Splicing Predictions 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!) 01/03/2013UK NEQAS UV Participants Meeting 201312

13. 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 01/03/2013UK NEQAS UV Participants Meeting 201313

14. NGS Alignment Viewer 01/03/2013UK NEQAS UV Participants Meeting 201314

15. 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 Missense Predictions 4.9 Splice Site Predictions 4.14 Interpretation Process Standardization 5.1 Reporting Variants 5.4 Variant Classification 01/03/2013UK NEQAS UV Participants Meeting 201315

16. 01/03/2013UK NEQAS UV Participants Meeting 201316 34 labs