rs199587998

Positions:

chr5-90629537-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The ENST00000405460.9(ADGRV1):c.1837C>A(p.Gln613Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000997 in 1,598,244 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 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 0.00053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0010 ( 1 hom. )

Consequence

ADGRV1
ENST00000405460.9 missense, splice_region

Scores

Splicing: ADA: 0.02066

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:7

Conservation

PhyloP100: 3.67

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036755443).

BP6

Variant 5-90629537-C-A is Benign according to our data. Variant chr5-90629537-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163564.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=3}. Variant chr5-90629537-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.1837C>A	p.Gln613Lys	missense_variant, splice_region_variant	9/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.1837C>A	p.Gln613Lys	missense_variant, splice_region_variant	9/90	1	NM_032119.4	ENSP00000384582	P1	Q8WXG9-1
ADGRV1	ENST00000504142.2 linkuse as main transcript	n.603C>A		splice_region_variant, non_coding_transcript_exon_variant	3/14	5
ADGRV1	ENST00000640109.1 linkuse as main transcript	n.1933C>A		non_coding_transcript_exon_variant	9/9	5

Frequencies

GnomAD3 genomes

AF:

0.000533

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000911

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000831

AC:

201

AN:

241892

Hom.:

AF XY:

0.000820

AC XY:

108

AN XY:

131778

show subpopulations

Gnomad AFR exome

AF:

0.000655

Gnomad AMR exome

AF:

0.0000297

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000294

Gnomad NFE exome

AF:

0.00165

Gnomad OTH exome

AF:

0.000512

GnomAD4 exome

AF:

0.00105

AC:

1512

AN:

1446154

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

729

AN XY:

719754

show subpopulations

Gnomad4 AFR exome

AF:

0.000183

Gnomad4 AMR exome

AF:

0.000115

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000172

Gnomad4 NFE exome

AF:

0.00132

Gnomad4 OTH exome

AF:

0.000653

GnomAD4 genome

AF:

0.000533

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000911

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.000586

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00109

AC:

ESP6500EA

AF:

0.00196

AC:

ExAC

AF:

0.00102

AC:

123

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 28, 2015	- -

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 07, 2016	p.Gln613Lys in exon 9 of GPR98: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, 7 mammals (cat, dog, panda, ferret, Pacific walrus, Weddell seal, and star- nosed mole) have a lysine (Lys) at this position despite high nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has also been identified in 0.2% (110/64 552) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs199587998). -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 19, 2018	The ADGRV1 c.1837C>A; p.Gln613Lys variant (rs199587998), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 163564). This variant is found in the non-Finnish European population with an overall allele frequency of 0.15% (191/123646 alleles) in the Genome Aggregation Database. The glutamine at codon 613 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Gln613Lys variant is uncertain at this time. -

Usher syndrome type 2C

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Retinitis pigmentosa

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

DBGen Ocular Genomics

Jun 16, 2021

- -

ADGRV1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 10, 2023

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

0.091

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.087

T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.75

.;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.037

T;T

MetaSVM

Benign

-0.75

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.4

.;N

REVEL

Benign

0.051

Sift

Benign

0.13

.;T

Sift4G

Benign

0.070

.;T

Polyphen

0.052

B;B

Vest4

0.24

MVP

0.62

MPC

0.057

ClinPred

0.058

GERP RS

4.6

Varity_R

0.30

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.021

dbscSNV1_RF

Benign

0.28

SpliceAI score (max)

0.020

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