rs41303344

Positions:

chr5-90627284-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_032119.4(ADGRV1):c.746G>A(p.Arg249Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00936 in 1,609,410 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. R249R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0065 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0097 ( 88 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:13

Conservation

PhyloP100: 2.15

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045897663).

BP6

Variant 5-90627284-G-A is Benign according to our data. Variant chr5-90627284-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46374.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=6}. Variant chr5-90627284-G-A is described in Lovd as [Likely_benign]. Variant chr5-90627284-G-A is described in Lovd as [Benign]. Variant chr5-90627284-G-A is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0065 (987/151812) while in subpopulation NFE AF= 0.0108 (735/67898). AF 95% confidence interval is 0.0102. There are 7 homozygotes in gnomad4. There are 453 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.746G>A	p.Arg249Lys	missense_variant	7/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.746G>A	p.Arg249Lys	missense_variant	7/90	1	NM_032119.4	P1	Q8WXG9-1
ADGRV1	ENST00000640281.1 linkuse as main transcript	n.805G>A		non_coding_transcript_exon_variant	7/7	1
ADGRV1	ENST00000640083.1 linkuse as main transcript	n.451G>A		non_coding_transcript_exon_variant	5/6	5
ADGRV1	ENST00000640109.1 linkuse as main transcript	n.842G>A		non_coding_transcript_exon_variant	7/9	5

Frequencies

GnomAD3 genomes

AF:

0.00651

AC:

987

AN:

151694

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00407

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00333

Gnomad FIN

AF:

0.00872

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0108

Gnomad OTH

AF:

0.00577

GnomAD3 exomes

AF:

0.00639

AC:

1581

AN:

247404

Hom.:

AF XY:

0.00667

AC XY:

895

AN XY:

134162

show subpopulations

Gnomad AFR exome

AF:

0.00149

Gnomad AMR exome

AF:

0.00404

Gnomad ASJ exome

AF:

0.00233

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00318

Gnomad FIN exome

AF:

0.00880

Gnomad NFE exome

AF:

0.00955

Gnomad OTH exome

AF:

0.00684

GnomAD4 exome

AF:

0.00966

AC:

14074

AN:

1457598

Hom.:

Cov.:

AF XY:

0.00930

AC XY:

6742

AN XY:

724650

show subpopulations

Gnomad4 AFR exome

AF:

0.00144

Gnomad4 AMR exome

AF:

0.00437

Gnomad4 ASJ exome

AF:

0.00336

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00370

Gnomad4 FIN exome

AF:

0.00766

Gnomad4 NFE exome

AF:

0.0113

Gnomad4 OTH exome

AF:

0.00832

GnomAD4 genome

AF:

0.00650

AC:

987

AN:

151812

Hom.:

Cov.:

AF XY:

0.00610

AC XY:

453

AN XY:

74218

show subpopulations

Gnomad4 AFR

AF:

0.00143

Gnomad4 AMR

AF:

0.00407

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00333

Gnomad4 FIN

AF:

0.00872

Gnomad4 NFE

AF:

0.0108

Gnomad4 OTH

AF:

0.00571

Alfa

AF:

0.00949

Hom.:

Bravo

AF:

0.00597

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.0121

AC:

ExAC

AF:

0.00611

AC:

738

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00961

EpiControl

AF:

0.00778

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:8

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 09, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2018	This variant is associated with the following publications: (PMID: 28041643, 32581362) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ADGRV1: BP4, BS1, BS2 -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 17, 2023	Variant summary: ADGRV1 c.746G>A (p.Arg249Lys) results in a conservative amino acid change in 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 0.0064 in 247404 control chromosomes, predominantly at a frequency of 0.0096 within the Non-Finnish European subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.78 fold of the estimated maximal expected allele frequency for a pathogenic variant in ADGRV1 causing Usher Syndrome phenotype (0.0054), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.746G>A has been reported in the literature in one individual affected with Inherited Retinal Disease (Carss_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as VUS (n=1), Benign (n=4), Likely Benign (n=2) and Likely Pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 26, 2012	Arg249Lys in exon 7 of GPR98: This variant is not expected to have clinical sign ificance because it has been identified in 1.17% (77/6554) of European American chromosomes and 0.17% (5/2954) of African American chromosomes in a broad popula tion by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/; d bSNP rs41303344). -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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 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

0.086

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.047

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.53

.;T

MetaRNN

Benign

0.0046

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.66

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.1

.;N

REVEL

Benign

0.035

Sift

Benign

0.26

.;T

Sift4G

Benign

0.23

.;T

Polyphen

0.0060

B;B

Vest4

0.18

MVP

0.40

MPC

0.11

ClinPred

0.0064

GERP RS

4.0

Varity_R

0.070

gMVP

0.49

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