Submissions for variant NM_139276.3(STAT3):c.551-4G>A

gnomAD frequency: 0.00109  dbSNP: rs80162032

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000909520	SCV001054332	benign	Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function	2025-01-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193227	SCV001361951	benign	not specified	2019-03-01	criteria provided, single submitter	clinical testing	Variant summary: STAT3 c.551-4G>A 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. 4/4 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 0.00046 in 276526 control chromosomes, predominantly at a frequency of 0.0037 within the African subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African control individuals in the gnomAD database is approximately 1682 fold of the estimated maximal expected allele frequency for a pathogenic variant in STAT3 causing Hyper IgE Syndrome phenotype (2.2e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.551-4G>A in individuals affected with Hyper IgE Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory, University of Chicago	RCV001193227	SCV002065747	benign	not specified	2020-10-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003968374	SCV004784156	likely benign	STAT3-related disorder	2019-08-29	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).