Large-scale sequencing of the human population has shaped the current understanding of naturally occurring genetic sequence variation. Each human genome contains approximately 3 million to 5 million variants, including approximately 30 000 variants in protein-coding genes, when compared with the reference genome. In the case of mendelian conditions, only 1 or 2 of these variants may be relevant to a molecular diagnosis. Many lines of evidence are required to determine whether a particular variant is likely to cause or contribute to the development of disease, but one powerful discriminator is allele frequency. Allele frequency is defined as the proportion of alleles (2 per individual) that carry a particular variant at a specific location in the genome.
Whiffin N, Ware JS, O’Donnell-Luria A. Improving the Understanding of Genetic Variants in Rare Disease With Large-scale Reference Populations. JAMA. 2019;322(13):1305–1306. doi:10.1001/jama.2019.12891
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