rs200945405

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_032119.4(ADGRV1):c.3443G>A(p.Gly1148Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,603,510 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1148V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 8 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:8

Conservation

PhyloP100: 9.72

Publications

15 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: Likely_benign. The variant received -4 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 5-90652372-G-A is Benign according to our data. Variant chr5-90652372-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46316.

BS2

High Homozygotes in GnomAdExome4 at 8 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4 link	c.3443G>A	p.Gly1148Asp	missense_variant	Exon 19 of 90	ENST00000405460.9	NP_115495.3	Q8WXG9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADGRV1	ENST00000405460.9 link	c.3443G>A	p.Gly1148Asp	missense_variant	Exon 19 of 90	1	NM_032119.4	ENSP00000384582.2	Q8WXG9-1
ADGRV1	ENST00000640403.1 link	c.746G>A	p.Gly249Asp	missense_variant	Exon 9 of 29	5		ENSP00000492531.1	A0A1W2PRC7
ADGRV1	ENST00000504142.2 link	n.2209G>A		non_coding_transcript_exon_variant	Exon 13 of 14	5
ADGRV1	ENST00000639676.1 link	n.1041G>A		non_coding_transcript_exon_variant	Exon 7 of 11	5

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

243

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00333

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00240

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00182

AC:

445

AN:

243888

AF XY:

0.00192

show subpopulations

Gnomad AFR exome

AF:

0.000584

Gnomad AMR exome

AF:

0.00144

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000233

Gnomad NFE exome

AF:

0.00257

Gnomad OTH exome

AF:

0.00118

GnomAD4 exome

AF:

0.00233

AC:

3387

AN:

1451312

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

1727

AN XY:

720816

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

33236

American (AMR)

AF:

0.00176

AC:

AN:

43694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25804

East Asian (EAS)

AF:

0.00

AC:

AN:

39560

South Asian (SAS)

AF:

0.00273

AC:

225

AN:

82382

European-Finnish (FIN)

AF:

0.000640

AC:

AN:

53130

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00264

AC:

2924

AN:

1107804

Other (OTH)

AF:

0.00175

AC:

105

AN:

59972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

149

298

448

597

746

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

224

336

448

560

<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:

0.00160

AC:

243

AN:

152198

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.000458

AC:

AN:

41528

American (AMR)

AF:

0.00196

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00333

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.000660

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00240

AC:

163

AN:

68012

Other (OTH)

AF:

0.00332

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00217

Hom.:

Bravo

AF:

0.00167

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000525

AC:

ESP6500EA

AF:

0.00266

AC:

ExAC

AF:

0.00182

AC:

220

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Aug 16, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 10, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25133751, 28041643, 27068579, 25404053, 24154662) -

not specified

Benign:3

Sep 11, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Gly1148Asp in exon 19 of GPR98: This variant is not expected to have clinical significance because it has been identified in 0.3% (50/16450) of South Asian ch romosomes and 0.2% (149/66614) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200945405). -

Feb 14, 2023

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.3443G>A (p.Gly1148Asp) results in a non-conservative amino acid change located in the Na-Ca exchanger/integrin-beta4 domain (IPR003644) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 243888 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 (0.0018 vs 0.0054). c.3443G>A has been reported in the literature primarily in settings of multigene panel sequencing in individuals affected with retinopathies and/or deafness without strong evidence for causality and in at least one case where an alternative cause for the phenotype was identified (e.g. Aparisi_2014, Wang_2014, Watson_2014, Sommen_2016, Zampaglione_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, classifying the variant as either VUS (n=4), likely benign (n=3) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Apr 04, 2024

Athena Diagnostics

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

- -

Usher syndrome type 2C

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Retinal dystrophy

Uncertain:1

Dec 05, 2018

Blueprint Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2

Benign:1

Sep 07, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

ADGRV1-related disorder

Benign:1

Jun 25, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Febrile seizures, familial, 4;C2931213:Usher syndrome type 2C

Benign:1

Apr 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T;.

Eigen

Uncertain

0.64

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

.;T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.026

T;T;T

MetaSVM

Uncertain

-0.098

PhyloP100

9.7

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.9

.;D;.

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

.;D;.

Polyphen

1.0

D;D;.

Vest4

0.93

MVP

0.75

MPC

0.34

ClinPred

0.051

GERP RS

6.1

Varity_R

0.89

gMVP

0.89

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.53

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.53

Position offset: 23

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