rs374609813

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_032119.4(ADGRV1):​c.2261T>C​(p.Val754Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000868 in 1,613,274 control chromosomes in the GnomAD database, including 4 homozygotes. 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: š‘“ 0.000066 ( 1 hom., cov: 33)
Exomes š‘“: 0.000089 ( 3 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

7
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.71
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 Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.067183465).
BP6
Variant 5-90642656-T-C is Benign according to our data. Variant chr5-90642656-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178356.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
BS2
High Homozygotes in GnomAdExome4 at 3 AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADGRV1NM_032119.4 linkc.2261T>C p.Val754Ala missense_variant Exon 12 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.2261T>C p.Val754Ala missense_variant Exon 12 of 90 1 NM_032119.4 ENSP00000384582.2 Q8WXG9-1
ADGRV1ENST00000640403 linkc.-437T>C 5_prime_UTR_variant Exon 2 of 29 5 ENSP00000492531.1 A0A1W2PRC7
ADGRV1ENST00000504142.2 linkn.1027T>C non_coding_transcript_exon_variant Exon 6 of 14 5
ADGRV1ENST00000639676.1 linkn.-235T>C upstream_gene_variant 5

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152158
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000141
AC:
35
AN:
248760
Hom.:
2
AF XY:
0.000207
AC XY:
28
AN XY:
134966
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000720
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000976
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000890
AC:
130
AN:
1461116
Hom.:
3
Cov.:
32
AF XY:
0.000125
AC XY:
91
AN XY:
726816
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:
0.000789
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000468
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152158
Hom.:
1
Cov.:
33
AF XY:
0.000108
AC XY:
8
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000174
Hom.:
0
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000245
AC:
2
ExAC
AF:
0.000207
AC:
25
EpiCase
AF:
0.000273
EpiControl
AF:
0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 29, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The Val754Ala variant in GPR98 has not been previously reported in individuals w ith hearing loss, but has been identified in 0.03% (2/8154) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs374609813). Although this variant has been seen in the general po pulation, its frequency is not high enough to rule out a pathogenic role. Compu tational prediction tools and conservation analyses do not provide strong suppor t for or against an impact to the protein. In summary, the clinical significance of the Val754Ala variant is uncertain. -

not provided Benign:1
Oct 31, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.12
T;T
Eigen
Uncertain
0.24
Eigen_PC
Uncertain
0.32
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.82
.;T
M_CAP
Benign
0.053
D
MetaRNN
Benign
0.067
T;T
MetaSVM
Benign
-1.1
T
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-1.5
.;N
REVEL
Benign
0.15
Sift
Uncertain
0.0070
.;D
Sift4G
Uncertain
0.0050
.;D
Polyphen
0.68
P;P
Vest4
0.58
MVP
0.61
MPC
0.18
ClinPred
0.15
T
GERP RS
5.1
Varity_R
0.17
gMVP
0.56

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: rs374609813; hg19: chr5-89938473; API