Abstract
Variant pathogenicity classifiers such as SIFT, PolyPhen-2, CADD, and MetaLR assist in interpretation of the hundreds of rare, missense variants in the typical patient genome by deprioritizing some variants as likely benign. These widely used methods misclassify 26 to 38% of known pathogenic mutations, which could lead to missed diagnoses if the classifiers are trusted as definitive in a clinical setting. We developed M-CAP, a clinical pathogenicity classifier that outperforms existing methods at all thresholds and correctly dismisses 60% of rare, missense variants of uncertain significance in a typical genome at 95% sensitivity.
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Acknowledgements
We thank the members of the Bejerano laboartory, particularly J. Notwell, S. Chinchali, and J. Birgmeier, for technical advice and helpful discussions. P.D.S. and D.N.C. receive financial support from Qiagen through a license agreement with Cardiff University. We thank the PolyPhen-2, CADD, Eigen, FATHMM, MutationTaster, and MetaLR teams for making their training and testing data readily available. This work was funded in part by the Stanford Pediatrics Department, DARPA, a Packard Foundation Fellowship, and a Microsoft Faculty Fellowship to G.B.
Author information
Author notes
- Karthik A Jagadeesh
- & Aaron M Wenger
These authors contributed equally to this work.
Affiliations
Department of Computer Science, Stanford University, Stanford, California, USA.
- Karthik A Jagadeesh
- , Mark J Berger
- & Gill Bejerano
Department of Pediatrics, Stanford University, Stanford, California, USA.
- Aaron M Wenger
- , Harendra Guturu
- , Jonathan A Bernstein
- & Gill Bejerano
Department of Medical Genetics, Cardiff University, Heath Park, Cardiff, UK.
- Peter D Stenson
- & David N Cooper
Department of Developmental Biology, Stanford University, Stanford, California, USA.
- Gill Bejerano
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Contributions
K.A.J., A.M.W., M.J.B., and G.B. designed the study and analyzed results. K.A.J. and M.J.B. implemented the model and performed the experiments. K.A.J., A.M.W., and H.G. wrote software tools that were used for analysis. P.D.S. and D.N.C. curated the HGMD data and provided feedback. J.A.B. provided patient exome cases and feedback. K.A.J., A.M.W., and G.B. wrote the manuscript. All authors reviewed and commented on the manuscript.
Competing interests
The authors declare no competing financial interests.
Corresponding author
Correspondence to Gill Bejerano.
Supplementary information
PDF files
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Supplementary Text and Figures
Supplementary Tables 1–4, 6, 9 and 10.
Excel files
- 1.
Supplementary Table 5
M-CAP scores for disease-causing mutations found in BRCA1, BRCA2, CFTR and MLL2.
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Supplementary Table 7
Clinical phenotypes for case study patients.
- 3.
Supplementary Table 8
Rare missense variants in case study patients.
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