Table 1

Text descriptors from selected bioinformatic prediction programmes used for variant annotation in sequencing pipelines*

ProgrammeOutput terms and other descriptions
CONsensus DELeteriousness score of missense mutations (CONDEL) Deleterious
Neutral
(http://bg.upf.edu/fannsdb/)
Description: the scores of different methods (SIFT, Polyphen2, Mutation Assessor, FATHMM, Ensembl-variation) are weighted using the complementary cumulative distributions of approximately 20 000 missense SNPs, both deleterious and neutral.
Functional Analysis through Hidden Markov Models (FATHMM)Damaging
Tolerated
(http://fathmm.biocompute.org.uk)
Likelihood Ratio Test (LRT) Deleterious
Disease-causing (identified in a ‘mutation database’)
Polymorphism (predicted OR annotated) (http://www.genetics.wustl.edu/jflab/lrt_query.html)
Mutation taster Deleterious
Neutral
Unknown (http://www.mutationtaster.org)
Mutation assessor Predicted non-functional (low, neutral)
Predicted functional (low, neutral) (http://mutationassessor.org)
Predicting disease-associated non-synonymous SNPs Analyzer (nsSNPAnalyzer)Disease
Neutral
(http://snpanalyzer.uthsc.edu/)
Predictor of human deleterious SNPs (PhD-SNP)Disease
Neutral
(http://snps.biofold.org/phd-snp/)
Polymorphism Phenotyping v2 (PolyPhen-2) Probably damaging
Possibly damaging
Benign
(http://genetics.bwh.harvard.edu/pph2)
Protein Variation Effect Analyzer (Provean) Deleterious
Neutral
(http://provean.jcvi.org)
Sorting Intolerant From Tolerant (SIFT) Damaging
Tolerated
(http://sift-dna.org)
  • *Prediction tools used for missense variants denoted in bold are included as options for scoring bioinformatic predictions in the ClinGen Pathogenicity calculator40 (http://calculator.clinicalgenome.org/site/cg-calculator), and the ClinGen Variant Curation Interface (https://curation.clinicalgenome.org/), both developed to enable application of the ACMG/AMP guidelines. The meta-predictors Rare Exome Variant Ensemble Learner (REVEL),41 Combined Annotation Dependent Depletion (CADD)42 and BayesDel,43 provide continuous scores and not specific terms as output. Output terms also used in clinical reporting, or to define eligibility for poly ADP ribose polymerase inhibitor treatment, are noted in italics.

  • ACMG, American College of Medical Genetics and Genomics; AMP, Association for Molecular Pathology.