chr5-90716722-G-A

Position:

chr5-90716722-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032119.4(ADGRV1):c.9440G>A(p.Arg3147Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,610,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R3147R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7B:1

Conservation

PhyloP100: 3.25

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]

ADGRV1 links:

LOC105379077 (HGNC:):

LOC105379077 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.025375962).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.9440G>A	p.Arg3147Gln	missense_variant	43/90	ENST00000405460.9
LOC105379077	XR_001742802.2 linkuse as main transcript	n.364-913C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.9440G>A	p.Arg3147Gln	missense_variant	43/90	1	NM_032119.4	P1	Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.000362

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000302

AC:

AN:

248466

Hom.:

AF XY:

0.000297

AC XY:

AN XY:

134858

show subpopulations

Gnomad AFR exome

AF:

0.000517

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000160

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000218

AC:

318

AN:

1458406

Hom.:

Cov.:

AF XY:

0.000219

AC XY:

159

AN XY:

725606

show subpopulations

Gnomad4 AFR exome

AF:

0.000599

Gnomad4 AMR exome

AF:

0.00134

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:

0.000197

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000361

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000140

Hom.:

Bravo

AF:

0.000518

ESP6500AA

AF:

0.000551

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000199

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 24, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2017	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 14, 2024	Variant summary: ADGRV1 c.9440G>A (p.Arg3147Gln) 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 0.0003 in 248466 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ADGRV1 causing Usher Syndrome (0.0003 vs 0.0054), allowing no conclusion about variant significance. c.9440G>A has been reported in the literature in individuals affected with Usher Syndrome, progressive hearing loss and epilepsy, often reported in cis with c.1718G>T (p.Gly573Val) (Neveling_2013, Sharon_2020, Dahawi_2021). 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 publications have been ascertained in the context of this evaluation (PMID: 34744978, 24123792, 31456290). ClinVar contains an entry for this variant (Variation ID: 46290). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 04, 2020	The p.Arg3147Gln variant in ADGRV1 (also known as GPR98) has been previously reported in 5 individuals with hearing loss (Neveling 2013, LMM data), 4 of whom also carried the p.Gly573Val variant of uncertain significance in ADGRV1. These two variants were determined to be in cis in 1 individual tested at our laboratory. The p.Arg3147Gln variant has also been reported in ClinVar (Variation ID # 46404) as of uncertain significance. It has also been identified in 0.1% (42/35316) of Latino chromosomes at a similar frequency as the p.Gly573Val variant (0.1%; 41/35348 Latino chromosomes) by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200792658 and dbSNP rs200789563). Collectively, these data suggest that these variants are in linkage disequilibrium and are in cis in all reported individuals identified thus far. Moreover, arginine (Arg) at position 3147 is not conserved in mammals or evolutionarily distant species. Of note, 2 mammals (Elephant and Opossum) carry a glutamine (Gln) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg3147Gln variant is uncertain. ACMG/AMP criteria applied: BS1_Supporting, BP4. -

Usher syndrome type 2

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Idiopathic generalized epilepsy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Paris Brain Institute, Inserm - ICM

- -

Febrile seizures, familial, 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Institute of Human Genetics, University Hospital of Duesseldorf

- -

Usher syndrome type 2C

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

ADGRV1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 15, 2024

The ADGRV1 c.9440G>A variant is predicted to result in the amino acid substitution p.Arg3147Gln. This variant was reported along with a second missense variant (c.1718G>T, p.Gly573Val) in three siblings with progressive hearing loss with unreported phase (Neveling et al. 2013. PubMed ID: 24123792), in a cohort of patients with inherited retinal disease (Table S2, Sharon et al. 2019. PubMed ID: 31456290), and in cis phase in one individual with epilepsy (Dahawi et al. 2021. PubMed ID: 34744978). Based on internal data, the c.1718G>T and c.9440G>A variants are frequently detected together, suggesting that they are often found in cis. This variant is reported in 0.12% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.016

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

.;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.025

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.6

.;N

REVEL

Benign

0.070

Sift

Benign

0.095

.;T

Sift4G

Pathogenic

0.0

.;D

Polyphen

0.090

B;B

Vest4

0.14

MVP

0.41

MPC

0.26

ClinPred

0.034

GERP RS

3.2

Varity_R

0.23

gMVP

0.61

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over