ClinVar

Description

Variant summary: AIRE c.1567-5C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0027 in 274874 control chromosomes, predominantly at a frequency of 0.0095 within the South Asian subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in AIRE causing Autoimmune Polyglandular Syndrome Type 1 phenotype (0.0028), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.1567-5C>T in individuals affected with Autoimmune Polyglandular Syndrome Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "benign." Based on the evidence outlined above, the variant was classified as benign.