rs186999408

Positions:

chr5-90685822-C-T

Variant summary

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

The NM_032119.4(ADGRV1):c.6317C>T(p.Ala2106Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,611,320 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts 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. A2106A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0018 ( 6 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

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]

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=0.007327318).

BP6

Variant 5-90685822-C-T is Benign according to our data. Variant chr5-90685822-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46351.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=3, Uncertain_significance=2}. Variant chr5-90685822-C-T is described in Lovd as [Benign]. Variant chr5-90685822-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 6 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.6317C>T	p.Ala2106Val	missense_variant	29/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.6317C>T	p.Ala2106Val	missense_variant	29/90	1	NM_032119.4	ENSP00000384582	P1	Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.00255

AC:

387

AN:

151954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00566

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000965

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00193

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00145

AC:

358

AN:

247656

Hom.:

AF XY:

0.00131

AC XY:

176

AN XY:

134378

show subpopulations

Gnomad AFR exome

AF:

0.00536

Gnomad AMR exome

AF:

0.000499

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00362

Gnomad SAS exome

AF:

0.000492

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00156

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.00179

AC:

2611

AN:

1459248

Hom.:

Cov.:

AF XY:

0.00166

AC XY:

1207

AN XY:

725954

show subpopulations

Gnomad4 AFR exome

AF:

0.00565

Gnomad4 AMR exome

AF:

0.000471

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00101

Gnomad4 SAS exome

AF:

0.000465

Gnomad4 FIN exome

AF:

0.000170

Gnomad4 NFE exome

AF:

0.00200

Gnomad4 OTH exome

AF:

0.00134

GnomAD4 genome

AF:

0.00255

AC:

388

AN:

152072

Hom.:

Cov.:

AF XY:

0.00233

AC XY:

173

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00567

Gnomad4 AMR

AF:

0.000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000967

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0000946

Gnomad4 NFE

AF:

0.00193

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00202

Hom.:

Bravo

AF:

0.00273

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00709

AC:

ESP6500EA

AF:

0.00194

AC:

ExAC

AF:

0.00161

AC:

195

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00120

EpiControl

AF:

0.00143

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2019	This variant is associated with the following publications: (PMID: 22135276) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2021	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Ala2106Val in Exon 29 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (22/3118) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS). -

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. -

ADGRV1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2020

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

0.26

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;T;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

.;T;T

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.0073

T;T;T

MetaSVM

Benign

-0.72

MutationTaster

Benign

1.0

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.4

.;N;.

REVEL

Uncertain

0.36

Sift

Benign

0.036

.;D;.

Sift4G

Pathogenic

0.0

.;D;.

Polyphen

1.0

D;D;.

Vest4

0.89

MVP

0.74

MPC

0.32

ClinPred

0.052

GERP RS

5.8

Varity_R

0.26

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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