chr5-90652372-G-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_032119.4(ADGRV1):c.3443G>A(p.Gly1148Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,603,510 control chromosomes in the GnomAD database, including 8 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: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 8 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:7

Conservation

PhyloP100: 9.72

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, max_spliceai, FATHMM_MKL, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, MetaRNN, MutationTaster was below the threshold]

BS2

High Homozygotes in GnomAdExome4 at 8 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4 link	c.3443G>A	p.Gly1148Asp	missense_variant	Exon 19 of 90	ENST00000405460.9	NP_115495.3	Q8WXG9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADGRV1	ENST00000405460.9 link	c.3443G>A	p.Gly1148Asp	missense_variant	Exon 19 of 90	1	NM_032119.4	ENSP00000384582.2	Q8WXG9-1
ADGRV1	ENST00000640403.1 link	c.746G>A	p.Gly249Asp	missense_variant	Exon 9 of 29	5		ENSP00000492531.1	A0A1W2PRC7
ADGRV1	ENST00000504142.2 link	n.2209G>A		non_coding_transcript_exon_variant	Exon 13 of 14	5
ADGRV1	ENST00000639676.1 link	n.1041G>A		non_coding_transcript_exon_variant	Exon 7 of 11	5

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

243

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00333

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00240

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00182

AC:

445

AN:

243888

Hom.:

AF XY:

0.00192

AC XY:

253

AN XY:

131982

show subpopulations

Gnomad AFR exome

AF:

0.000584

Gnomad AMR exome

AF:

0.00144

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00315

Gnomad FIN exome

AF:

0.000233

Gnomad NFE exome

AF:

0.00257

Gnomad OTH exome

AF:

0.00118

GnomAD4 exome

AF:

0.00233

AC:

3387

AN:

1451312

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

1727

AN XY:

720816

show subpopulations

Gnomad4 AFR exome

AF:

0.000481

Gnomad4 AMR exome

AF:

0.00176

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00273

Gnomad4 FIN exome

AF:

0.000640

Gnomad4 NFE exome

AF:

0.00264

Gnomad4 OTH exome

AF:

0.00175

GnomAD4 genome

AF:

0.00160

AC:

243

AN:

152198

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.000458

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00333

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.00240

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00216

Hom.:

Bravo

AF:

0.00167

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000525

AC:

ESP6500EA

AF:

0.00266

AC:

ExAC

AF:

0.00182

AC:

220

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2025	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 16, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2021	This variant is associated with the following publications: (PMID: 25133751, 28041643, 27068579, 25404053, 24154662) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 04, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2023	Variant summary: ADGRV1 c.3443G>A (p.Gly1148Asp) results in a non-conservative amino acid change located in the Na-Ca exchanger/integrin-beta4 domain (IPR003644) of 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 0.0018 in 243888 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in ADGRV1 causing Usher Syndrome (0.0018 vs 0.0054). c.3443G>A has been reported in the literature primarily in settings of multigene panel sequencing in individuals affected with retinopathies and/or deafness without strong evidence for causality and in at least one case where an alternative cause for the phenotype was identified (e.g. Aparisi_2014, Wang_2014, Watson_2014, Sommen_2016, Zampaglione_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, classifying the variant as either VUS (n=4), likely benign (n=3) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 11, 2016	p.Gly1148Asp in exon 19 of GPR98: This variant is not expected to have clinical significance because it has been identified in 0.3% (50/16450) of South Asian ch romosomes and 0.2% (149/66614) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200945405). -

Usher syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Usher syndrome type 2C

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Dec 05, 2018

- -

ADGRV1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Febrile seizures, familial, 4;C2931213:Usher syndrome type 2C

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T;.

Eigen

Uncertain

0.64

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

.;T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.026

T;T;T

MetaSVM

Uncertain

-0.098

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.9

.;D;.

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

.;D;.

Polyphen

1.0

D;D;.

Vest4

0.93

MVP

0.75

MPC

0.34

ClinPred

0.051

GERP RS

6.1

Varity_R

0.89

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.53

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.53

Position offset: 23

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