rs183319660

Positions:

chr5-90745264-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_032119.4(ADGRV1):c.10768A>T(p.Ser3590Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000714 in 1,567,928 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 2 hom. )

Consequence

ADGRV1
NM_032119.4 missense, splice_region

Scores

Splicing: ADA: 0.9784

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.50

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:

ADGRV1 (HGNC:):

ADGRV1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03485784).

BS2

High Homozygotes in GnomAdExome4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.10768A>T	p.Ser3590Cys	missense_variant, splice_region_variant	51/90	ENST00000405460.9	NP_115495.3	Q8WXG9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.10768A>T	p.Ser3590Cys	missense_variant, splice_region_variant	51/90	1	NM_032119.4	ENSP00000384582.2		Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000227

AC:

AN:

224386

Hom.:

AF XY:

0.000229

AC XY:

AN XY:

122326

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00125

Gnomad ASJ exome

AF:

0.00102

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000281

Gnomad OTH exome

AF:

0.000370

GnomAD4 exome

AF:

0.0000671

AC:

AN:

1415644

Hom.:

Cov.:

AF XY:

0.0000712

AC XY:

AN XY:

702498

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.000844

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000174

Gnomad4 OTH exome

AF:

0.000136

GnomAD4 genome

AF:

0.000112

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000906

Hom.:

Bravo

AF:

0.000219

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 28, 2020	The ADGRV1 c.10768A>T; p.Ser3590Cys variant (rs183319660) is reported in the literature in an individual affected with Usher syndrome who also carried a homozygous MYO7A variant (Bonnet 2016). This variant is reported in ClinVar (Variation ID: 505525), and is found in the Latino population with an allele frequency of 0.12% (38/30556 alleles, including a single homozygote) in the Genome Aggregation Database. The serine at codon 3590 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Other computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site, however without functional studies, the effect on splicing is unknown. Due to limited information, the clinical significance of the p.Ser3590Cys variant is uncertain at this time. References: Bonnet et al. An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients. Eur J Hum Genet. 2016 Dec;24(12):1730-1738. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2020	This variant is associated with the following publications: (PMID: 27460420) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2022	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 3590 of the ADGRV1 protein (p.Ser3590Cys). This variant is present in population databases (rs183319660, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with ADGRV1-related conditions. ClinVar contains an entry for this variant (Variation ID: 505525). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 13, 2016

The p.Ser3590Cys variant in GPR98 has been previously reported in 1 individual w ith type 1 Usher syndrome explained by a homozygous variant in another gene (Bon net 2016). The p.Ser3590Cys variant has been reported in 0.1% (36/31300) of Lat ino chromosomes by the Genome Aggregation Consortium (gnomAD, http://gnomad.broa dinstitute.org; dbSNP rs183319660). Computational prediction tools and conserva tion analyses suggest that this variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. Furthermore, this variant is located in the last three bases of the exon, which is part of the 5' splice region. Computational tools do not suggest an impact to splicing. However , this information is not predictive enough to rule out pathogenicity. In summar y, the clinical significance of the p.Ser3590Cys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;T

Eigen

Benign

0.064

Eigen_PC

Benign

-0.0058

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.84

.;T

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.035

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.1

.;D

REVEL

Benign

0.15

Sift

Benign

0.043

.;D

Sift4G

Uncertain

0.0040

.;D

Polyphen

1.0

D;D

Vest4

0.54

MVP

0.59

MPC

0.32

ClinPred

0.22

GERP RS

3.1

Varity_R

0.24

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Benign

0.68

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

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