The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) framework for classifying variants uses six evidence categories related to the splicing potential of variants: PVS1, PS3, PP3, BS3, BP4, and BP7. However, the lack of guidance on how to apply such codes has contributed to variation in the specifications developed by different Clinical Genome Resource (ClinGen) Variant Curation Expert Panels. The ClinGen Sequence Variant Interpretation Splicing Subgroup was established to refine recommendations for applying ACMG/AMP codes relating to splicing data and computational predictions. We utilized empirically derived splicing evidence to (1) determine the evidence weighting of splicing-related data and appropriate criteria code selection for general use, (2) outline a process for integrating splicing-related considerations when developing a gene-specific PVS1 decision tree, and (3) exemplify methodology to calibrate splice prediction tools. We...
| Authors | Walker, LC; Hoya, M; Wiggins, GAR; Lindy, A; Vincent, LM; Parsons, MT; Canson, DM; Bis-Brewer, D; Cass, A; Tchourbanov, A; Zimmermann, H; Byrne, AB; Pesaran, T; Karam, R; Harrison, SM; Spurdle, AB; ClinGen Sequence Variant Interpretation Working Group |
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| Journal | AMERICAN JOURNAL OF HUMAN GENETICS |
| Pages | 1046-1067 |
| Volume | 110 |
| Date | 22/07/2023 |
| Grant ID | R01 CA264971 | NCI NIH HHS [CA] (United States); U24 HG006834 | NHGRI NIH HHS [HG] (United States); U24 HG009649 | NHGRI NIH HHS [HG] (United States); U24 HG009650 | NHGRI NIH HHS [HG] (United States) |
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| URL | http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1016/j.ajhg.2023.06.002 |