REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants.
The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p < 10-12) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies <0.5%. The area under the receiver operating characteristic curve (AUC) for REVEL was 0.046-0.182 higher in an independent test set of 935 recent SwissVar disease variants and 123,935 putatively neutral exome sequencing variants and 0.027-0.143 higher in an independent test set of 1,953 pathogenic and 2,406 benign variants recently reported in ClinVar than the AUCs for other ensemble methods. We provide pre-computed REVEL scores for all possible human missense variants to facilitate the identification of pathogenic variants in the sea of rare variants discovered as sequencing studies expand in scale.
Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA.
Nilah M
NM
Ioannidis
Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Joseph H
JH
Rothstein
Department of Computer Science and Informatics, Indiana University, Bloomington, IN 47405, USA.
Vikas
V
Pejaver
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Sumit
S
Middha
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
Shannon K
SK
McDonnell
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
Saurabh
S
Baheti
Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA.
Anthony
A
Musolf
Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA.
Qing
Q
Li
Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA.
Emily
E
Holzinger
Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
Danielle
D
Karyadi
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA.
Lisa A
LA
Cannon-Albright
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA.
Craig C
CC
Teerlink
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Janet L
JL
Stanford
Brady Urological Institute, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
William B
WB
Isaacs
NorthShore University HealthSystem Research Institute, Evanston, IL 60201, USA.
Jianfeng
J
Xu
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA; Departments of Internal Medicine and Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Kathleen A
KA
Cooney
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Ethan M
EM
Lange
Department of Medical Biochemistry and Genetics, University of Turku, Turku 20014, Finland; Department of Medical Genetics, Tyks Microbiology and Genetics, Turku University Hospital, Turku 20520, Finland.
Johanna
J
Schleutker
Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
John D
JD
Carpten
Department of Urology, Wayne State University, Detroit, MI 48201, USA.
Isaac J
IJ
Powell
Centre de Recherche sur les Pathologies Prostatiques et Urologiques, Universite Paris, Paris, 75013, France.
Olivier
O
Cussenot
Centre de Recherche sur les Pathologies Prostatiques et Urologiques, Universite Paris, Paris, 75013, France.
Geraldine
G
Cancel-Tassin
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia; Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, VIC 3010, Australia.
Graham G
GG
Giles
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia; Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, VIC 3010, Australia.
Robert J
RJ
MacInnis
Institute of Human Genetics, University Hospital of Ulm, Ulm 89075, Germany; Department of Urology, University Hospital of Ulm, Ulm 89075, Germany.
Christiane
C
Maier
Department of Urology, University of Southern California, Los Angeles, CA 90033, USA.
Chih-Lin
CL
Hsieh
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77, Sweden.
Fredrik
F
Wiklund
Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
William J
WJ
Catalona
Departments of Oncology and Human Genetics, Montreal General Hospital, Montreal, QC H3G 1A4, Canada.
William D
WD
Foulkes
Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Diptasri
D
Mandal
Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG, UK.
Rosalind A
RA
Eeles
Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG, UK.
Zsofia
Z
Kote-Jarai
Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA.
Carlos D
CD
Bustamante
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
Daniel J
DJ
Schaid
Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA; Department of Statistics, Stanford University, Stanford, CA 94305, USA.
Trevor
T
Hastie
Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
Elaine A
EA
Ostrander
Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA.
Joan E
JE
Bailey-Wilson
Department of Computer Science and Informatics, Indiana University, Bloomington, IN 47405, USA.
Predrag
P
Radivojac
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
Stephen N
SN
Thibodeau
Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA; Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA.
Alice S
AS
Whittemore
Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: weiva.sieh@mssm.edu.
Weiva
W
Sieh
D019540:Area Under Curve; D004252:DNA Mutational Analysis; D004194:Disease / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005787:Gene Frequency; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics*; D012372:ROC Curve; D012984:Software
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