Table 1.
Overview of the Prediction Tools Used in This Study
| Tool (abbreviation) | Version | N | AA | Purpose, as stated by developers |
|---|---|---|---|---|
| PolyPhen‐2 (PP2) | 2.2.2 | Yes | Yes | “Predicts possible impact of an amino acid substitution on the structure and function of a human protein using straightforward physical and comparative considerations”a |
| MutationTaster‐2 (MT2) | 2 | Yes | No | “Evaluation of the disease‐causing potential of DNA sequence alterations”b |
| MutationAssessor (MASS) | 2 | Yes | Yes | “Predicts the functional impact of amino acid substitutions in proteins, such as mutations discovered in cancer or missense polymorphisms”c |
| LRT | ‐ | Yes | No | “Identify a subset of deleterious mutations that disrupt highly conserved amino acids within protein‐coding sequences, which are likely to be unconditionally deleterious”d |
| SIFT | 1.03 | Yes | Yes | “Predicts whether an amino acid substitution affects protein function”e |
| GERP++ | – | Yes | No | “Identifies constrained elements in multiple alignments by quantifying substitution deficits. These deficits represent substitutions that would have occurred if the element were neutral DNA, but did not occur because the element has been under functional constraint. We refer to these deficits as “rejected substitutions.” Rejected substitutions are a natural measure of constraint that reflects the strength of past purifying selection on the element”f |
| phyloP | – | Yes | No | “Compute conservation or acceleration P values based on an alignment and a model of neutral evolution”g |
| FatHMM unweighted (FatHMM‐U) | 2.2–2.3 | No | Yes | Predicts “functional consequences of both coding variants, that is, nonsynonymous single‐nucleotide variants, and noncoding variants”h |
| FatHMM weighted (FatHMM‐W) | 2.2–2.3 | No | Yes | Predicts “functional consequences of both coding variants, that is, nonsynonymous single‐nucleotide variants, and noncoding variants” and its weighting scheme attributes higher tolerance scores to SNVs in proteins, related proteins, or domains that already include a high fraction of pathogenic variantsh |
| Combined Annotation Dependent Depletion (CADD) | 1.0 | Yes | No | “CADD is a tool for scoring the deleteriousness of single‐nucleotide variants as well as insertion/deletions variants in the human genome”i |
For each tool, the first column shows the version of the tool, the second column (N) shows whether it accepts nucleotide changes as input, the third column (AA) shows whether it accepts amino acid changes as input. The last column provides a description of the tool, as stated by the developers.