Figure 5
From: The functional spectrum of low-frequency coding variation
The distribution of functionally characterized Exon Pilot SNPs according to minor allele frequency within all samples. (a) Annotation according to amino acid change. The distribution of the Exon Pilot coding SNPs classified according to amino acid change introduced by the alternative allele (silent, missense, and nonsense) is shown, as a function of AF. Both missense and nonsense variants are enriched in the rare allele frequency bin compared to silent variants, with highly significant P << 10-16. The differences remain significant after correcting for the differential error rates in different bins (P << 10-16 for missense, and P << 10-5 for nonsense). (b) Computational prediction of functional impact. The distribution of SNPs classified according to functional impact (benign, possibly damaging, and damaging) based on computational predictions by the SIFT and PolyPhen-2 programs, as a function of allele frequency. In case of disagreement, the more severe classification was used. Silent SNPs are also shown, as neutral internal control for each bin. The damaging variants are highly enriched in the rare bin compared to the silent variants with highly significant P << 10-16. This remains significant after correcting for the differential error rates in different bins (P << 10-16). (a-b) Allele frequency was binned as follows: low frequency, <0.01; intermediate frequency, 0.01 to 0.1; and common, >0.1. The fraction of SNPs also called in the 1000 Genomes Low Coverage Pilot is indicated by blue shading, in each category. (c) Functional impact among variants shared with HGMD. Functional predictions using SIFT and PolyPhen-2 for the variants shared between the Exon Pilot and HGMD-DM, as a function of the disease allele frequency bin (<0.01, 0.01 to 0.1, and >0.1). Color represents predicted damage (green, benign; orange, possibly damaging; red, damaging); open sections represent variants shared between the Exon Pilot and Low Coverage Pilot, while solid sections represent variants observed only in the Exon Pilot.