A general framework for estimating the relative pathogenicity of human genetic variants

Details

• Alternative Title:
  Nat Genet
• Personal Author:
  Kircher, Martin ; Witten, Daniela M. ; Jain, Preti ; O’Roak, Brian J. ; Cooper, Gregory M. ; Shendure, Jay
• Description:
  Current methods for annotating and interpreting human genetic variation tend to exploit a single information type (for example, conservation) and/or are restricted in scope (for example, to missense changes). Here we describe Combined Annotation-Dependent Depletion (CADD), a method for objectively integrating many diverse annotations into a single measure (C score) for each variant. We implement CADD as a support vector machine trained to differentiate 14.7 million high-frequency human-derived alleles from 14.7 million simulated variants. We precompute C scores for all 8.6 billion possible human single-nucleotide variants and enable scoring of short insertions-deletions. C scores correlate with allelic diversity, annotations of functionality, pathogenicity, disease severity, experimentally measured regulatory effects and complex trait associations, and they highly rank known pathogenic variants within individual genomes. The ability of CADD to prioritize functional, deleterious and pathogenic variants across many functional categories, effect sizes and genetic architectures is unmatched by any current single-annotation method.
• Keywords:
  • Genetic Variation
  • Genome, Human
  • Genome-Wide Association Study
  • Humans
  • INDEL Mutation
  • Models, Genetic
  • Molecular Sequence Annotation
  • Polymorphism, Single Nucleotide
  • Selection, Genetic
  • Support Vector Machine
• Source:
  Nat Genet. 46(3):310-315
• Pubmed ID:
  24487276
• Pubmed Central ID:
  PMC3992975
• Document Type:
  Journal Article
• Funding:
  U54 HG006493/HG/NHGRI NIH HHSUnited States/ ; U54HG006493/HG/NHGRI NIH HHSUnited States/ ; DP1HG007811/DP/NCCDPHP CDC HHSUnited States/ ; DP1 HG007811/HG/NHGRI NIH HHSUnited States/ ; DP5OD009145/OD/NIH HHSUnited States/ ; DP5 OD009145/OD/NIH HHSUnited States/ ; UM1 HG006493/HG/NHGRI NIH HHSUnited States/
• Volume:
  46
• Issue:
  3
• Download URL:
  https://stacks.cdc.gov/view/cdc/25597/cdc_25597_DS1.pdf
• File Type:
  [PDF - 1.35 MB]
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:8fb19690359bad927edb0d0b2fc0b90ba8c7388f970ec40d092003480e219e90