rs190922596

Positions:

Variant summary

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

The NM_032119.4(ADGRV1):c.3191A>C(p.Glu1064Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,613,958 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 7 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:7

Conservation

PhyloP100: 0.937

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:

ADGRV1 (HGNC:):

ADGRV1 links:

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=0.007806927).

BP6

Variant 5-90647666-A-C is Benign according to our data. Variant chr5-90647666-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46312.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=3}. Variant chr5-90647666-A-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 7 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.3191A>C	p.Glu1064Ala	missense_variant	17/90	ENST00000405460.9	NP_115495.3	Q8WXG9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.3191A>C	p.Glu1064Ala	missense_variant	17/90	1	NM_032119.4	ENSP00000384582.2	Q8WXG9-1
ADGRV1	ENST00000640403.1 linkuse as main transcript	c.494A>C	p.Glu165Ala	missense_variant	7/29	5		ENSP00000492531.1	A0A1W2PRC7
ADGRV1	ENST00000504142.2 linkuse as main transcript	n.1957A>C		non_coding_transcript_exon_variant	11/14	5
ADGRV1	ENST00000639676.1 linkuse as main transcript	n.789A>C		non_coding_transcript_exon_variant	5/11	5

Frequencies

GnomAD3 genomes

AF:

0.00190

AC:

289

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00268

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00206

AC:

513

AN:

249068

Hom.:

AF XY:

0.00197

AC XY:

266

AN XY:

135106

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.00310

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00246

Gnomad NFE exome

AF:

0.00298

Gnomad OTH exome

AF:

0.00199

GnomAD4 exome

AF:

0.00212

AC:

3096

AN:

1461660

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

1463

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00293

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00247

Gnomad4 NFE exome

AF:

0.00244

Gnomad4 OTH exome

AF:

0.00195

GnomAD4 genome

AF:

0.00189

AC:

288

AN:

152298

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

139

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.00307

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.00266

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00202

Hom.:

Bravo

AF:

0.00171

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000528

AC:

ESP6500EA

AF:

0.00268

AC:

ExAC

AF:

0.00218

AC:

264

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 21, 2017	p.Glu1064Ala in exon 17 of ADGRV1: This variant is not expected to have clinical significance because it has been identified in 0.3% (371/126508) of European ch romosomes including one homozygote by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org; dbSNP rs190922596). ACMG?AMP criteria applied: BS1 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 12, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2014	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ADGRV1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2020	This variant is associated with the following publications: (PMID: 23804846, 22334370) -

Febrile seizures, familial, 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 27, 2013

- -

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. -

Retinitis pigmentosa

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

DBGen Ocular Genomics

Jan 01, 2021

Class 3 ACMG Guidelines, 2015 -

ADGRV1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.072

T;T;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.60

.;T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.0078

T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.0

.;N;.

REVEL

Benign

0.054

Sift

Benign

0.35

.;T;.

Sift4G

Benign

0.15

.;T;.

Polyphen

0.0010

B;B;.

Vest4

0.051

MVP

0.37

MPC

0.050

ClinPred

0.0045

GERP RS

3.3

Varity_R

0.11

gMVP

0.31

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