rs183319660
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The ENST00000405460.9(ADGRV1):c.10768A>T(p.Ser3590Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000714 in 1,567,928 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
ENST00000405460.9 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ADGRV1 | NM_032119.4 | c.10768A>T | p.Ser3590Cys | missense_variant, splice_region_variant | 51/90 | ENST00000405460.9 | NP_115495.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ADGRV1 | ENST00000405460.9 | c.10768A>T | p.Ser3590Cys | missense_variant, splice_region_variant | 51/90 | 1 | NM_032119.4 | ENSP00000384582 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000227 AC: 51AN: 224386Hom.: 1 AF XY: 0.000229 AC XY: 28AN XY: 122326
GnomAD4 exome AF: 0.0000671 AC: 95AN: 1415644Hom.: 2 Cov.: 25 AF XY: 0.0000712 AC XY: 50AN XY: 702498
GnomAD4 genome AF: 0.000112 AC: 17AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74450
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 25, 2022 | This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 3590 of the ADGRV1 protein (p.Ser3590Cys). This variant is present in population databases (rs183319660, gnomAD 0.1%). 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: 505525). 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. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 18, 2020 | This variant is associated with the following publications: (PMID: 27460420) - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 28, 2020 | The ADGRV1 c.10768A>T; p.Ser3590Cys variant (rs183319660) is reported in the literature in an individual affected with Usher syndrome who also carried a homozygous MYO7A variant (Bonnet 2016). This variant is reported in ClinVar (Variation ID: 505525), and is found in the Latino population with an allele frequency of 0.12% (38/30556 alleles, including a single homozygote) in the Genome Aggregation Database. The serine at codon 3590 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Other computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site, however without functional studies, the effect on splicing is unknown. Due to limited information, the clinical significance of the p.Ser3590Cys variant is uncertain at this time. References: Bonnet et al. An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients. Eur J Hum Genet. 2016 Dec;24(12):1730-1738. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 13, 2016 | The p.Ser3590Cys variant in GPR98 has been previously reported in 1 individual w ith type 1 Usher syndrome explained by a homozygous variant in another gene (Bon net 2016). The p.Ser3590Cys variant has been reported in 0.1% (36/31300) of Lat ino chromosomes by the Genome Aggregation Consortium (gnomAD, http://gnomad.broa dinstitute.org; dbSNP rs183319660). Computational prediction tools and conserva tion analyses suggest that this variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. Furthermore, this variant is located in the last three bases of the exon, which is part of the 5' splice region. Computational tools do not suggest an impact to splicing. However , this information is not predictive enough to rule out pathogenicity. In summar y, the clinical significance of the p.Ser3590Cys variant is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at