Submissions for variant NM_021008.4(DEAF1):c.56T>C (p.Val19Ala)

gnomAD frequency: 0.00124  dbSNP: rs767318857

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000502415	SCV000594352	uncertain significance	not specified	2016-01-22	criteria provided, single submitter	clinical testing
Invitae	RCV001857089	SCV002170860	uncertain significance	not provided	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 19 of the DEAF1 protein (p.Val19Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with DEAF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 434935). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DEAF1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV001857089	SCV003834316	uncertain significance	not provided	2022-05-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541555	SCV004759893	likely benign	DEAF1-related disorder	2022-08-30	criteria provided, single submitter	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356171	SCV001551262	uncertain significance	Intellectual disability-epilepsy-extrapyramidal syndrome		no assertion criteria provided	clinical testing	The DEAF1 p.V19A variant was identified in the literature as a somatic variant in a tumor sample from a patient with Biliary Tract Cancer (Yoon_2018_PMID:30602096). The variant was identified in dbSNP (ID: rs767318857) and ClinVar (classified as uncertain significance by University of Chicago, Genetic Services Laboratory). The variant was identified in control databases in 72 of 57852 chromosomes at a frequency of 0.001245, and was observed at the highest frequency in the European (non-Finnish) population in 50 of 27362 chromosomes (freq: 0.001827) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.V19 residue is not highly conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.