rs41303344

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). 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

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:14

Conservation

PhyloP100: 2.15

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

Usher syndrome type 2
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 2C
Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
febrile seizures, familial, 4
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ADGRV1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 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 Benign/Likely_benign. ClinVar VariationId is 46374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4 link	c.746G>A	p.Arg249Lys	missense_variant	Exon 7 of 90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ADGRV1	ENST00000405460.9 link	c.746G>A	p.Arg249Lys	missense_variant	Exon 7 of 90	1	NM_032119.4	ENSP00000384582.2
ADGRV1	ENST00000640281.1 link	n.805G>A		non_coding_transcript_exon_variant	Exon 7 of 7	1
ADGRV1	ENST00000640083.1 link	n.451G>A		non_coding_transcript_exon_variant	Exon 5 of 6	5
ADGRV1	ENST00000640109.1 link	n.842G>A		non_coding_transcript_exon_variant	Exon 7 of 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

GnomAD2 exomes

AF:

0.00639

AC:

1581

AN:

247404

AF XY:

0.00667

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 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

African (AFR)

AF:

0.00144

AC:

AN:

33388

American (AMR)

AF:

0.00437

AC:

195

AN:

44572

Ashkenazi Jewish (ASJ)

AF:

0.00336

AC:

AN:

25928

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.00370

AC:

317

AN:

85790

European-Finnish (FIN)

AF:

0.00766

AC:

408

AN:

53238

Middle Eastern (MID)

AF:

0.00157

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0113

AC:

12509

AN:

1109068

Other (OTH)

AF:

0.00832

AC:

501

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

673

1347

2020

2694

3367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

484

968

1452

1936

2420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00650

AC:

987

AN:

151812

Hom.:

Cov.:

AF XY:

0.00610

AC XY:

453

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.00143

AC:

AN:

41396

American (AMR)

AF:

0.00407

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.00333

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00872

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0108

AC:

735

AN:

67898

Other (OTH)

AF:

0.00571

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

109

163

218

272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00887

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: Benign/Likely benign

Submissions summary: Pathogenic:1Uncertain:1Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ADGRV1: BP4, BS1, BS2 -

Jun 21, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 19, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28041643, 32581362) -

Aug 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:5

Mar 26, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 2 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. The following publications have been ascertained in the context of this evaluation (PMID: 28041643, 32420686, 33089500). ClinVar contains an entry for this variant (Variation ID: 46374). Based on the evidence outlined above, the variant was classified as likely benign. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 19, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome

Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Retinal dystrophy

Uncertain:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Usher syndrome type 2C

Benign:1

Apr 08, 2025

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

2.1

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

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over