rs199499672
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_032119.4(ADGRV1):c.9643G>A(p.Glu3215Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000306 in 1,610,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00031 ( 0 hom. )
Consequence
ADGRV1
NM_032119.4 missense
NM_032119.4 missense
Scores
1
8
9
Clinical Significance
Conservation
PhyloP100: 5.87
Genes affected
ADGRV1 (HGNC:17416): (adhesion G protein-coupled receptor V1) This gene encodes a member of the G-protein coupled receptor superfamily. The encoded protein contains a 7-transmembrane receptor domain, binds calcium and is expressed in the central nervous system. Mutations in this gene are associated with Usher syndrome 2 and familial febrile seizures. Several alternatively spliced transcripts have been described. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2791213).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ADGRV1 | NM_032119.4 | c.9643G>A | p.Glu3215Lys | missense_variant | 45/90 | ENST00000405460.9 | NP_115495.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ADGRV1 | ENST00000405460.9 | c.9643G>A | p.Glu3215Lys | missense_variant | 45/90 | 1 | NM_032119.4 | ENSP00000384582.2 |
Frequencies
GnomAD3 genomes AF: 0.000237 AC: 36AN: 152080Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000290 AC: 72AN: 248528Hom.: 0 AF XY: 0.000311 AC XY: 42AN XY: 134846
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GnomAD4 exome AF: 0.000315 AC: 459AN: 1458406Hom.: 0 Cov.: 29 AF XY: 0.000328 AC XY: 238AN XY: 725554
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GnomAD4 genome AF: 0.000223 AC: 34AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74422
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 20, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 15, 2024 | Identified in the heterozygous state in a patient with epilepsy and cardiac conduction disorder in published literature (PMID: 29261713); Identified as a single heterozygous variant in a patient with panuveitis in published literature (PMID: 32707200); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29261713, 32707200) - |
Usher syndrome type 2C Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Laboratory of Prof. Karen Avraham, Tel Aviv University | Dec 26, 2024 | The ADGRV1 c.9643G>A:p.(Glu3215Lys) heterozygous variant is very rare and predicted deleterious. This variant was classified as likely pathogenic by Deafness Variation Database, and according to ClinVar SCV000063351.5, it was detected in hearing impaired individuals. In our study, it was detected in an individual with sloping normal-to-severe HL, that carried another variant in USH1G,c.955A>G:p.(Arg319Gly), suggesting digenic inheritance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 25, 2018 | The p.Glu3215Lys variant in ADGRV1 has been previously reported by our laborator y in 2 individuals with hearing loss, one of whom also harbored a second ADGRV1 variant of uncertain significance (trans/cis not yet determined). The variant wa s also identified in 51/126478 European chromosomes by the Genome Aggregation Da tabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199499672). However, t his frequency is not high enough to rule out a pathogenic role. Computational pr ediction tools and conservation analysis suggest that this variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the p.Glu32215Lys variant is un certain. ACMG/AMP Criteria applied: PP3. - |
Febrile seizures, familial, 4;C2931213:Usher syndrome type 2C Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
PrimateAI
Benign
T
PROVEAN
Uncertain
.;D
REVEL
Benign
Sift
Uncertain
.;D
Sift4G
Uncertain
.;D
Polyphen
P;P
Vest4
0.56
MVP
0.73
MPC
0.072
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at