rs876657817

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_032119.4(ADGRV1):​c.11411G>A​(p.Arg3804Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,024 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R3804R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

6
9
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 8.61
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADGRV1NM_032119.4 linkc.11411G>A p.Arg3804Gln missense_variant Exon 55 of 90 ENST00000405460.9 NP_115495.3 Q8WXG9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADGRV1ENST00000405460.9 linkc.11411G>A p.Arg3804Gln missense_variant Exon 55 of 90 1 NM_032119.4 ENSP00000384582.2 Q8WXG9-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152106
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460918
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
726786
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152106
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:2
Mar 14, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Arg3804Gln variant in GPR98 has not been previously reported in individual s with hearing loss or Usher syndrome and is absent from large population studie s. Computational prediction tools and conservation analyses suggest that the p.A rg3804Gln variant may impact the protein, though this information is not predict ive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg3804Gln variant is uncertain. -

Feb 10, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: ADGRV1 c.11411G>A (p.Arg3804Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248926 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.11411G>A has been reported in the literature in two siblings from a family affected with hearing loss, without strong evidence for causality (Wu_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32048449). ClinVar contains an entry for this variant (Variation ID: 228704). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1
Mar 26, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 3804 of the ADGRV1 protein (p.Arg3804Gln). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with nonsyndromic deafness (PMID: 32048449). ClinVar contains an entry for this variant (Variation ID: 228704). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADGRV1 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.46
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.35
T;T;.
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.87
.;D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.92
D;D;D
MetaSVM
Uncertain
-0.076
T
PrimateAI
Benign
0.38
T
PROVEAN
Uncertain
-3.2
.;D;.
REVEL
Uncertain
0.52
Sift
Pathogenic
0.0
.;D;.
Sift4G
Uncertain
0.013
.;D;.
Polyphen
1.0
D;D;.
Vest4
0.69
MutPred
0.79
Loss of stability (P = 0.0482);Loss of stability (P = 0.0482);.;
MVP
0.81
MPC
0.30
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.96
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs876657817; hg19: chr5-90050833; COSMIC: COSV67998017; COSMIC: COSV67998017; API