rs727504706
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_032119.4(ADGRV1):c.13919G>A(p.Gly4640Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000244 in 1,557,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_032119.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152074Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000222 AC: 4AN: 180578Hom.: 0 AF XY: 0.0000312 AC XY: 3AN XY: 96236
GnomAD4 exome AF: 0.0000242 AC: 34AN: 1405520Hom.: 0 Cov.: 27 AF XY: 0.0000245 AC XY: 17AN XY: 694704
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152074Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74302
ClinVar
Submissions by phenotype
not provided Uncertain:3
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This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 4640 of the ADGRV1 protein (p.Gly4640Glu). This variant is present in population databases (rs727504706, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with ADGRV1-related conditions. ClinVar contains an entry for this variant (Variation ID: 179204). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
not specified Uncertain:2
Variant summary: ADGRV1 c.13919G>A (p.Gly4640Glu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 180578 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.13919G>A has been reported in the literature in individuals affected with ADGRV1-Related Disorders and many of these individuals also carry variants from other genes (Quesne Stabej_2012, Dahawi_2021, Ganapathi_2022). These report(s) do not provide unequivocal conclusions about association of the variant with ADGRV1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22135276, 34744978, 35672425). ClinVar contains an entry for this variant (Variation ID: 179204). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Variant classified as Uncertain Significance - Favor Benign. The p.Gly4640Glu va riant in GPR8 has been previously reported in one individual with Usher syndrome (Le Quesne Stabej 2012) and was identified by our laboratory in three individua ls with hearing loss; however, this variant was not thought to be related to the clinical features in these individuals due to the presence of an alternate expl anation of the hearing loss and/or non-segregation with disease in affected fami ly members. Data from large population studies are insufficient to assess the fr equency of this variant. Computational prediction tools and conservation analysi s suggest that the p.Gly4640Glu variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. In summary, the cli nical significance of the p.Gly4640Glu variant is uncertain; however, based on t he identification of this variant in several individuals with an alternate expla nation for their hearing loss suggests that it is more likely to be benign. -
Idiopathic generalized epilepsy Pathogenic:1
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Febrile seizures, familial, 4 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at