rs201386977

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_032119.4(ADGRV1):c.11974G>A(p.Asp3992Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,578,446 control chromosomes in the GnomAD database, including 5 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. D3992D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 5 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:5

Conservation

PhyloP100: 9.23

Publications

11 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0114889145).

BP6

Variant 5-90759442-G-A is Benign according to our data. Variant chr5-90759442-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178365.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00131 (199/152110) while in subpopulation AMR AF = 0.00445 (68/15272). AF 95% confidence interval is 0.0036. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4 link	c.11974G>A	p.Asp3992Asn	missense_variant	Exon 58 of 90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9 link	c.11974G>A	p.Asp3992Asn	missense_variant	Exon 58 of 90	1	NM_032119.4	ENSP00000384582.2

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

199

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00446

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00154

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00148

AC:

292

AN:

196962

AF XY:

0.00151

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00208

Gnomad ASJ exome

AF:

0.00594

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000260

Gnomad NFE exome

AF:

0.00173

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00131

AC:

1863

AN:

1426336

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

937

AN XY:

705916

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

32940

American (AMR)

AF:

0.00203

AC:

AN:

38496

Ashkenazi Jewish (ASJ)

AF:

0.00652

AC:

166

AN:

25462

East Asian (EAS)

AF:

0.00

AC:

AN:

38618

South Asian (SAS)

AF:

0.000746

AC:

AN:

81728

European-Finnish (FIN)

AF:

0.000232

AC:

AN:

51718

Middle Eastern (MID)

AF:

0.00384

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00129

AC:

1409

AN:

1092412

Other (OTH)

AF:

0.00186

AC:

110

AN:

59232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

170

254

339

424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.00131

AC:

199

AN:

152110

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41484

American (AMR)

AF:

0.00445

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00154

AC:

105

AN:

68014

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00172

Hom.:

Bravo

AF:

0.00139

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000252

AC:

ESP6500EA

AF:

0.00144

AC:

ExAC

AF:

0.000989

AC:

119

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 08, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25262649, 25404053, 27460420, 22952768, 30245029, 31047384, 32707200) -

Apr 26, 2018

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ADGRV1: BS2 -

Aug 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 12, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ADGRV1 p.Asp3992Asn variant was identified in 2 of 896 proband chromosomes (frequency: 0.002) from individuals or families with Usher syndrome (Eandi_2017_PMID:29142287; Bonnet_2016_PMID:27460420). The variant was also identified in dbSNP (ID: rs201386977), ClinVar (classified as a VUS by GeneDx, EGL Genetics, Athena Diagnostics, ARUP and Praxis fuer Humangenetik Tuebingen and as likely benign by Laboratory for Molecular Medicine) and LOVD 3.0. The variant was not identified in Cosmic. The variant was identified in control databases in 320 of 228350 chromosomes at a frequency of 0.001401 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 54 of 9380 chromosomes (freq: 0.005757), Latino in 60 of 28672 chromosomes (freq: 0.002093), Other in 11 of 6242 chromosomes (freq: 0.001762), European (non-Finnish) in 168 of 99320 chromosomes (freq: 0.001692), South Asian in 19 of 25506 chromosomes (freq: 0.000745), European (Finnish) in 5 of 22700 chromosomes (freq: 0.00022) and African in 3 of 20596 chromosomes (freq: 0.000146), while the variant was not observed in the East Asian population. The p.Asp3992 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Usher syndrome type 2C

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

Mar 14, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asp3992Asn in exon 58 of GPR98: This variant is not expected to have clinical significance because it has been identified in 0.4% (59/15416) of European chrom osomes and in 0.4% (4/944) of Latino chromosomes by the Exome Aggregation Consor tium (http://exac.broadinstitute.org/; dbSNP rs201386977). -

ADGRV1-related disorder

Benign:1

Jun 05, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;T;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.88

.;D;D

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

0.27

PhyloP100

9.2

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.5

.;D;.

REVEL

Uncertain

0.57

Sift

Benign

0.067

.;T;.

Sift4G

Pathogenic

0.0

.;D;.

Polyphen

1.0

D;D;.

Vest4

0.76

MVP

0.76

MPC

0.32

ClinPred

0.15

GERP RS

5.0

Varity_R

0.39

gMVP

0.91

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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