5-90629418-G-T

Position:

chr5-90629418-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032119.4(ADGRV1):c.1718G>T(p.Gly573Val) variant causes a missense change. The variant allele was found at a frequency of 0.000233 in 1,613,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:9B:1

Conservation

PhyloP100: 5.10

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15449491).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.1718G>T	p.Gly573Val	missense_variant	9/90	ENST00000405460.9	NP_115495.3	Q8WXG9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.1718G>T	p.Gly573Val	missense_variant	9/90	1	NM_032119.4	ENSP00000384582.2	Q8WXG9-1
ADGRV1	ENST00000504142.2 linkuse as main transcript	n.484G>T		non_coding_transcript_exon_variant	3/14	5
ADGRV1	ENST00000640109.1 linkuse as main transcript	n.1814G>T		non_coding_transcript_exon_variant	9/9	5

Frequencies

GnomAD3 genomes

AF:

0.000362

AC:

AN:

151794

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000556

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000951

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000297

AC:

AN:

249058

Hom.:

AF XY:

0.000289

AC XY:

AN XY:

135116

show subpopulations

Gnomad AFR exome

AF:

0.000517

Gnomad AMR exome

AF:

0.00119

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:

0.000159

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000220

AC:

321

AN:

1461588

Hom.:

Cov.:

AF XY:

0.000216

AC XY:

157

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00136

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000203

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000362

AC:

AN:

151912

Hom.:

Cov.:

AF XY:

0.000364

AC XY:

AN XY:

74210

show subpopulations

Gnomad4 AFR

AF:

0.000555

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000951

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000122

Hom.:

Bravo

AF:

0.000499

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000536

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000182

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 15, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2017	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 14, 2024	Variant summary: ADGRV1 c.1718G>T (p.Gly573Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 249058 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ADGRV1 causing Usher Syndrome (0.0003 vs 0.0054), allowing no conclusion about variant significance. c.1718G>T has been reported in the literature in individuals affected with Usher Syndrome, progressive hearing loss and epilepsy, often reported in cis with c.9440G>A (p.Arg3147Gln) (Neveling_2013, Sharon_2020, Dahawi_2021, Zhou_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34744978, 24123792, 31456290, 35813073). ClinVar contains an entry for this variant (Variation ID: 46290). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 04, 2020	The p.Gly573Val variant in ADGRV1 has been previously reported in 4 individuals with hearing loss (Neveling 2013, LMM data), all of whom also carried the p.Arg3147Gln variant of unknown significance in GPR98. These two variants were determined to be in cis in 1 individual tested at our laboratory. The p.Gly573Val variant has also been reported in ClinVar (Variation ID # 46290) as of uncertain significance. The p.Gly573Val variant has been identified in 0.1% (41/35348) of Latino chromosomes at a similar frequency of the p.Arg3147Gln variant at 0.1% (42/35316) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200789563 and rs200792658). All information collectively suggests that these variants are in linkage disequilibrium and are likely in cis in all of the reported individuals. Although the p.Gly753Val variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Additionally, computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: BS1_Supporting. -

Usher syndrome type 2

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Idiopathic generalized epilepsy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Paris Brain Institute, Inserm - ICM

- -

Febrile seizures, familial, 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Institute of Human Genetics, University Hospital of Duesseldorf

- -

Usher syndrome type 2C

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

ADGRV1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 15, 2024

The ADGRV1 c.1718G>T variant is predicted to result in the amino acid substitution p.Gly573Val. This variant was reported along with a second missense variant (c.9440G>A, p.Arg3147Gln) in three siblings with progressive hearing loss with unreported phase (Neveling et al. 2013. PubMed ID: 24123792), in a cohort of patients with inherited retinal disease (Table S2, Sharon et al. 2019. PubMed ID: 31456290), and in cis phase in one individual with epilepsy (Dahawi et al. 2021. PubMed ID: 34744978). Based on internal data, the c.1718G>T and c.9440G>A variants are frequently detected together, suggesting that they are often found in cis. This variant is reported in 0.12% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.80

.;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.33

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.8

.;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0040

.;D

Sift4G

Uncertain

0.010

.;D

Polyphen

1.0

D;D

Vest4

0.76

MVP

0.67

MPC

0.34

ClinPred

0.087

GERP RS

4.6

Varity_R

0.59

gMVP

0.80

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