be considered as pathological candidates) are much lower; 130-400 nonsynonymous variants per individual, 10-20 LOF variants, 2-5 damaging mutations and 1-2 variants identified previously from cancer genome sequencing25. By comparison to synonymous variants, we can estimate the excess of rare variants; those mutations that are sufficiently deleterious that they will never reach high frequency. We estimate that individuals carry an excess of 76-190 rare deleterious nonsynonymous variants and up to 20 LOF and disease-associated variants. Interestingly, the overall excess of low-frequency variants is similar to that of rare variants (Table 2). Because many variants contributing to disease risk are likely to be segregating at low frequency, we recommend that variant frequency be considered when using the resource to identify pathological candidates.
