RVIS (Residual Variation Intolerance Score) is a gene-based score intended to help in the interpretation of human sequence data. The intolerance score in its current form is based upon allele frequency data as represented in whole exome sequence data from the NHLBI-ESP6500 data set. The score is designed to rank genes in terms of whether they have more or less common functional genetic variation relative to the genome wide expectation given the amount of apparently neutral variation the gene has. A gene with a positive score has more common functional variation, and a gene with a negative score has less and is referred to as "intolerant". By convention we rank all genes in order from most intolerant to least. As an example, a gene such as ATP1A3 has a RVIS score of -1.53 and a percentile of 3.37%, meaning it is amongst the 3.37% most intolerant of human genes. Depending on what disease area you are a studying, you may way to consider either intolerant genes (neurodevelomental disease) or tolerant genes (some immunological diseases) as better candidates. Data sourced from: EVS-v.0.0.14, (June 20, 2012)

Currently this application accommodates genes within CCDS releases 9 to 20. It takes HGNC nomenclature for genes with at least one public CCDS transcript.

The newest RVIS release (v4) is based on the ExAC v2 standing variation data and relies on transcript information from CCDS release 20 and variant annotations from Ensembl release 87.

Note that for genes with very low (Y), there may not be enough polymorphism data represented in the population samples currently for an accurate assessment of genic intolerance. For this reason, genes where Y is below 10 and X is relatively small (<140) have the additional option of a simple comparison reported based on the observed and expected functional variation in the gene ("OE-ratio"). In this formulation, allele frequency is ignored, and we simply compare the ‘proportion of Observed non-synonymous variation’ over the ‘proportion of Expected non-synonymous variation.’ The “Expected proportion” is determined by simulating all possible single nucleotide substitutions from the underlying protein-coding sequence context of the gene. The reported OEratio score reflects how divergent the observed proportion is from the expected proportion, and this is converted to a genome-wide percentile. These percentiles are interpreted in the same ways as the RVIS formation. So that an edge case gene that scores as having a low OE-ratio statistic is also judged "intolerant." We are continuously working on a unified approach to capture those signals in a uniformed way across the genome.

ExAC_LoF_FDR: To generate the loss-of-function (LoF) deficiency measure “ExAC_LoF_FDR”, we apply our previously described methodology from Petrovski et al. (2015) on the larger ExAC cohort.

We took each gene's missense, synonymous and loss-of-function mutation rates (See: Exome Aggregation Consortium et al., 2016 (pre-print publication)) to calculate the gene’s expected frequency of protein-coding LoF variants (Ps). This was achieved by dividing the mutation rate associated with the simulated LoF variants to the overall genic mutation rate (sum of the three aforementioned mutation classes). The result is an estimate of the percentage of observed variants in a gene that we expect to be annotated as a LoF effect. We then use the ExAC database (release 0.3) to extract for each gene both the total number of observed unique variants (n) and specifically the number of observed unique LoF variants reported in that gene (x). This is the observed rate of LoF variants given all the protein-coding variation found in the gene within the ExAC reference cohort. Taking a gene’s expected rate of distinct LoF variation under neutrality as calculated by (Ps), a subset of 3,760 genes were identified as being significantly deficient of LoF variants using a one-sided binomial exact test with Benjamini & Hochberg false discovery rate multiple-testing correction (FDR = 1%) (See Petrovski et al. (2015) for more information based on the EVS implementation).

While a fraction of the exome non-informative for LoF deficiency due to insufficient resolution (power) and will improve with a larger reference cohort, the list of genes that are already significantly LoF deficient based on the ExAC data release is already a valuable resource.