ClinVar Miner

Submissions for variant NM_014423.4(AFF4):c.1835A>G (p.Asn612Ser)

gnomAD frequency: 0.00006  dbSNP: rs145031583
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001927340 SCV002166956 uncertain significance Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome 2023-12-09 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 612 of the AFF4 protein (p.Asn612Ser). This variant is present in population databases (rs145031583, gnomAD 0.02%). 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: 1394183). 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 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.
Ambry Genetics RCV002555222 SCV003569823 likely benign Inborn genetic diseases 2021-10-29 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences RCV003968619 SCV004785109 uncertain significance AFF4-related disorder 2023-10-31 criteria provided, single submitter clinical testing The AFF4 c.1835A>G variant is predicted to result in the amino acid substitution p.Asn612Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-132232487-T-C), which is more common than expected for an undocumented cause of disease. Although we suspect this variant may be benign, at this time, its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.

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