An individual's genome contains many variants of functional consequence, ranging from the beneficial to the highly deleterious. We estimated that an individual typically differs from the reference at 10,000-11,000 nonsynonymous sites (sequence differences that lead to differences in the protein sequence) in addition to 10,000-12,000 synonymous sites (differences in coding exons that do not lead to differences in the protein sequence; Table 2). We found a much smaller number of variants likely to have greater functional impact: in frame indels (190-210), premature stop codons (80-100), splice site disrupting variants (40-50), and deletions that shift reading frame (220-250), in each individual. We estimated that each genome is heterozygous for 50-100 variants classified by the Human Gene Mutation Database (HGMD) as causing inherited disorders (HGMD-DM). Estimates from the different pilot projects were consistent with each other, taking into consideration differences in power to detect low frequency variants, fraction of the accessible genome and population differences (Table 2), as well as with previous observations based on personal genome sequences10, 11. Collectively, we refer to the 340-400 premature stops, splice site disruptions and frame shifts, affecting 250-300 genes per individual, as putative loss of function (LOF) variants.
