PolyPhen-2 calculates a Naive Bayes posterior probability that any mutation is damaging by the representation of a score ranging from 0 to 1 and predicts qualitative damage based on the model's false positive rate (benign, possibly damaging, or probably damaging).
Within the prioritized variants, those harboring truncating mutations or mutations predicted to be damaging were considered to be the most promising candidates.
Considering living cells, this could correspond to the situation when parts of the enzyme are damaged by mutations (a case specifically relevant to mitochondria, where mutations, involving those in cytochrome b subunit of complex III, appear to accumulate with age [27]).
Both mutations were predicted to be damaging by the CADD algorithm, and one mutation (p.Asp27His) was predicted to be damaging by SIFT algorithm (Ng and Henikoff, 2001; Kircher et al., 2014).
Cancer begins when a cell undergoes a mutation: one or more of its genes are damaged or lost.
These three missense mutations were predicted to be damaging in functional prediction by SIFT and PolyPhen2.
Considering that about half of missense mutations are expected to be damaging to a typical protein [ 20], we expect that even a small allelic series will be useful for phenotypic analysis.
Functionally significant driver mutations affecting splicing are expected to comprise many of the same pathways implicated by protein coding mutations that are predicted to be damaging.
A color code was used to distinguish mutations that are predicted to be damaging by various numbers of the methods described above (zero in dark green, one in light green, two in orange yellow, three in brown, and four in red).
Two of the 13 mutations which were found to be damaging from SIFT and Polyphen results and which were common among patients were further examined in silico for 3D structural effects.
