Submissions for variant NM_000383.4(AIRE):c.1567-5C>T

gnomAD frequency: 0.00158  dbSNP: rs192215705

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000241567	SCV000051956	benign	not specified	2018-06-26	criteria provided, single submitter	clinical testing	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.
Eurofins Ntd Llc (ga)	RCV000241567	SCV000345077	benign	not specified	2016-08-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000029310	SCV000754675	benign	Polyglandular autoimmune syndrome, type 1	2024-02-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001091471	SCV001247538	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	AIRE: BP4, BS2
GeneDx	RCV001091471	SCV001828858	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003891443	SCV000303916	benign	AIRE-related disorder	2021-12-20	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV000029310	SCV001457193	benign	Polyglandular autoimmune syndrome, type 1	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001091471	SCV001931591	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001091471	SCV001974541	likely benign	not provided		no assertion criteria provided	clinical testing