rs200115167

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_032119.4(ADGRV1):c.14761G>A(p.Ala4921Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000777 in 1,610,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00057 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00080 ( 0 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.654

Publications

4 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029129028).

BP6

Variant 5-90805383-G-A is Benign according to our data. Variant chr5-90805383-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178370.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4 link	c.14761G>A	p.Ala4921Thr	missense_variant	Exon 72 of 90	ENST00000405460.9	NP_115495.3	Q8WXG9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9 link	c.14761G>A	p.Ala4921Thr	missense_variant	Exon 72 of 90	1	NM_032119.4	ENSP00000384582.2		Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000502

AC:

125

AN:

248982

AF XY:

0.000541

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000726

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000815

Gnomad OTH exome

AF:

0.000662

GnomAD4 exome

AF:

0.000798

AC:

1164

AN:

1458518

Hom.:

Cov.:

AF XY:

0.000775

AC XY:

562

AN XY:

725232

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33454

American (AMR)

AF:

0.000940

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.0000767

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.00

AC:

AN:

85920

European-Finnish (FIN)

AF:

0.0000750

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000943

AC:

1046

AN:

1109390

Other (OTH)

AF:

0.00106

AC:

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

111

167

222

278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

126

168

210

<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:

0.000571

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41578

American (AMR)

AF:

0.00170

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000779

AC:

AN:

68030

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.000746

Hom.:

Bravo

AF:

0.000948

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000268

AC:

ESP6500EA

AF:

0.000973

AC:

ExAC

AF:

0.000406

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:3

Sep 13, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ADGRV1 c.14761G>A; p.Ala4921Thr variant (rs200115167), to our knowledge, has not been reported in the medical literature; however, it is listed in the ClinVar database with conflicting interpretations of pathogenicity (Variation ID: 178370). This variant is found in the general population with an allele frequency in non-Finnish European populations of 0.00% (101/128,320 alleles) in the Genome Aggregation Database. The alanine at codon 4921 is moderately conserved (Alamut v.2.11) and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, based on the available information, the clinical significance of this variant is uncertain. -

Apr 29, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient with blindness due to alterations of the retina, choroid, vitreous, and/or optic nerve in published literature, however additional patient information was not provided (PMID: 32483926); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25468891, 25683121, 35593993, 32483926) -

Mar 20, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

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

- -

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

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Apr 24, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala4921Thr in exon 72 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 0.1% (8/8218) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; dbSNP rs200115167). Furthermore, this amino acid is not well conserved acr oss species and several mammals carry a threonine (Thr) at this position. -

Mar 03, 2025

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.14761G>A (p.Ala4921Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00078 in 1610862 control chromosomes, predominantly at a frequency of 0.0011 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in ADGRV1 causing ADGRV1-Related Disorders phenotype. c.14761G>A has been reported in the literature in at leadt one individual affected with blindness (e.g., Dineiro_2020). However, these report(s) do not provide unequivocal conclusions about association of the variant with ADGRV1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32483926). ClinVar contains an entry for this variant (Variation ID: 178370). Based on the evidence outlined above, the variant was classified as likely benign. -

Usher syndrome type 2

Uncertain:1

Apr 07, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Inborn genetic diseases

Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.14761G>A (p.A4921T) alteration is located in exon 72 (coding exon 72) of the ADGRV1 gene. This alteration results from a G to A substitution at nucleotide position 14761, causing the alanine (A) at amino acid position 4921 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.071

T;T;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.60

.;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.029

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

0.65

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.32

.;N;.

REVEL

Benign

0.036

Sift

Benign

0.35

.;T;.

Sift4G

Benign

0.69

.;T;.

Polyphen

0.0010

B;B;.

Vest4

0.066

MVP

0.17

MPC

0.047

ClinPred

0.0066

GERP RS

1.4

Varity_R

0.029

gMVP

0.18

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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