rs371970388

Positions:

chr5-90781575-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032119.4(ADGRV1):c.13228G>A(p.Glu4410Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,600,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.345

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054958284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4 link	c.13228G>A	p.Glu4410Lys	missense_variant	65/90	ENST00000405460.9	NP_115495.3	Q8WXG9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ADGRV1	ENST00000405460.9 link	c.13228G>A	p.Glu4410Lys	missense_variant	65/90	1	NM_032119.4	ENSP00000384582.2	Q8WXG9-1
ADGRV1	ENST00000638510.1 link	n.495G>A		non_coding_transcript_exon_variant	1/26	1
ADGRV1	ENST00000425867.3 link	c.2182G>A	p.Glu728Lys	missense_variant	13/38	5		ENSP00000392618.3	A0A1X7SBU6
ADGRV1	ENST00000639431.1 link	n.265+105366G>A		intron_variant		5		ENSP00000491057.1	A0A1W2PNS5

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000618

AC:

AN:

242614

Hom.:

AF XY:

0.0000304

AC XY:

AN XY:

131364

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000135

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000123

AC:

178

AN:

1448162

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

717992

show subpopulations

Gnomad4 AFR exome

AF:

0.0000906

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000150

Gnomad4 OTH exome

AF:

0.000134

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000193

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.0000547

EpiControl

AF:

0.000239

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2023	Observed with the G2756R variant in the ADGRV1 gene in a patient with myoclonic epilepsy in published literature (Myers et al., 2018); Observed with the G2756R variant in the ADGRV1 gene in unrelated patients referred for genetic testing at GeneDx, confirmed to be on the same allele (in cis) in a single case; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29266188, 34160719, 36399868, 32962041) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 06, 2024	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Polyphen and MutationTaster predict this amino acid change may be benign. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 28, 2017

Variant classified as Uncertain Significance - Favor Benign. The p.Glu4410Lys va riant in GPR98 has not been previously reported in individuals with Usher syndro me, but has been identified in 3/61466 European chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs371970388). Altho ugh this variant has been seen in the general population, its frequency is not h igh enough to rule out a pathogenic role. The glutamic acid (Glu) at position 44 10 is not conserved across species with two mammals (squirrel and aardvark) havi ng 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. In summary, while the clinical significance of the p.Glu4 410Lys variant is uncertain, available data suggest that it is more likely to be benign. -

Usher syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 26, 2020

Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as a 3C-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. 0108 - This gene is known to be associated with both recessive and dominant disease. 0200 - Variant is predicted to result in a missense amino acid change from a glutamic acid to a lysine (exon 65). 0304 - Variant is present in gnomAD <0.01 for recessive indication (18 heterozygotes, 0 homozygotes) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygotes). 0503 - Missense variant consistently predicted to be tolerated OR not conserved in mammals with a minor amino acid change. 0600 - Variant is located in an annotated domain or motif that does not have a well-established function (Calx-beta domain). 0705 - No comparable variants in relevant codon/region have previous evidence for pathogenicity. 0807 - Variant has not previously been reported in a clinical context. 0905 - No published segregation evidence has been identified for this variant. 1007 - No published functional evidence has been identified for this variant. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.13

T;T;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.20

LIST_S2

Uncertain

0.86

.;D;T

M_CAP

Benign

0.0089

MetaRNN

Benign

0.055

T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.0

.;N;.

REVEL

Benign

0.056

Sift

Benign

0.32

.;T;.

Sift4G

Benign

0.21

.;T;.

Polyphen

0.68

P;P;.

Vest4

0.17

MVP

0.31

MPC

0.072

ClinPred

0.062

GERP RS

1.4

Varity_R

0.037

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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