rs202190568

Positions:

chr5-90763396-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_032119.4(ADGRV1):c.12212G>A(p.Arg4071Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000839 in 1,613,418 control chromosomes in the GnomAD database, including 1 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 0.00070 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00085 ( 1 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: -0.411

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018234879).

BP6

Variant 5-90763396-G-A is Benign according to our data. Variant chr5-90763396-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178366.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}. Variant chr5-90763396-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.12212G>A	p.Arg4071Gln	missense_variant	59/90	ENST00000405460.9	NP_115495.3	Q8WXG9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.12212G>A	p.Arg4071Gln	missense_variant	59/90	1	NM_032119.4	ENSP00000384582.2		Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.000704

AC:

107

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00124

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000719

AC:

179

AN:

249010

Hom.:

AF XY:

0.000792

AC XY:

107

AN XY:

135094

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00130

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.000853

AC:

1247

AN:

1461328

Hom.:

Cov.:

AF XY:

0.000854

AC XY:

621

AN XY:

726952

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000206

Gnomad4 NFE exome

AF:

0.00103

Gnomad4 OTH exome

AF:

0.000862

GnomAD4 genome

AF:

0.000704

AC:

107

AN:

152090

Hom.:

Cov.:

AF XY:

0.000767

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.000386

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00124

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00120

Hom.:

Bravo

AF:

0.000672

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000852

AC:

ExAC

AF:

0.000646

AC:

EpiCase

AF:

0.00109

EpiControl

AF:

0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 04, 2017	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 09, 2022	Variant summary: ADGRV1 c.12212G>A (p.Arg4071Gln) results in a conservative amino acid change located in the Na-Ca exchanger/integrin-beta4 domain (IPR003644) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 249010 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 (0.00072 vs 0.0054), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.12212G>A in individuals affected with features of ADGRV1-Related Disorders such as Usher Syndrome type 2C or Familial Febrile Seizures 4 and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3; Likely Benign, n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 06, 2016	p.Arg4071Gln in exon 59 of GPR98: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, more than 10 different mammals have a glutamine (Gln) at this position despite high nearby amino acid conservation. In addition, this variant was iden tified in 0.1% (74/66372) of European chromosomes by the Exome Aggregation Conso rtium (ExAC, http://exac.broadinstitute.org; dbSNP rs202190568). -

Usher syndrome type 2C

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.73

CADD

Benign

4.5

DANN

Benign

0.61

DEOGEN2

Benign

0.047

T;T;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.70

.;T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.018

T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.20

PROVEAN

Benign

0.040

.;N;.

REVEL

Benign

0.014

Sift

Benign

0.45

.;T;.

Sift4G

Benign

0.32

.;T;.

Polyphen

0.032

B;B;.

Vest4

0.11

MVP

0.14

MPC

0.062

ClinPred

0.0079

GERP RS

-0.32

Varity_R

0.038

gMVP

0.32

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