Submissions for variant NM_014423.4(AFF4):c.2995A>G (p.Thr999Ala)

gnomAD frequency: 0.00001  dbSNP: rs780871066

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001870369	SCV002123323	uncertain significance	Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	2024-09-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 999 of the AFF4 protein (p.Thr999Ala). This variant is present in population databases (rs780871066, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with AFF4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1356977). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt AFF4 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.
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV001870369	SCV004041896	likely benign	Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	2023-10-13	criteria provided, single submitter	clinical testing	This variant has been identified by standard clinical testing. Selected ACMG criteria: Likely benign (I):BS2;BP4
PreventionGenetics, part of Exact Sciences	RCV003416507	SCV004118249	uncertain significance	AFF4-related disorder	2023-08-22	criteria provided, single submitter	clinical testing	The AFF4 c.2995A>G variant is predicted to result in the amino acid substitution p.Thr999Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-132223223-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV003883712	SCV004698869	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	AFF4: PP2, BP4, BS2