chr5-90840606-G-A

Position:

chr5-90840606-G-A

Variant summary

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

The NM_032119.4(ADGRV1):c.16640G>A(p.Arg5547His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000646 in 1,610,544 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 1 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 2.20

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 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=0.09433985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4 link	c.16640G>A	p.Arg5547His	missense_variant	78/90	ENST00000405460.9	NP_115495.3	Q8WXG9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9 link	c.16640G>A	p.Arg5547His	missense_variant	78/90	1	NM_032119.4	ENSP00000384582.2		Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000105

AC:

AN:

247702

Hom.:

AF XY:

0.0000968

AC XY:

AN XY:

134328

show subpopulations

Gnomad AFR exome

AF:

0.000453

Gnomad AMR exome

AF:

0.000262

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0000659

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.0000445

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000514

AC:

AN:

1458306

Hom.:

Cov.:

AF XY:

0.0000566

AC XY:

AN XY:

725014

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000105

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.0000830

GnomAD4 genome

AF:

0.000190

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000774

Hom.:

Bravo

AF:

0.000257

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.0000993

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2022	Reported in a patient with Meniere's disease in published literature (Roman-Naranjo et al., 2021); this patient also was found to have a heterozygous MYO7A variant; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27149842, 34391192) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 08, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Arg5547His va riant in GPR98 has not been previously reported in individuals with hearing loss , but has been identified in 12/117174 chromosomes across multiple populations b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200907244). The arginine (Arg) at position 5547 is not conserved in mammals or evolutionarily distant species, with 1 mammal (manatee) having a histidine (His ) at this position, suggesting that this change may be tolerated. Additional com putational prediction tools suggest that the p.Arg5547His variant may not impact the protein, though this information is not predictive enough to rule out patho genicity. In summary, while the clinical significance of the p.Arg5547His varian t is uncertain, its lack of evolutionarily conservation suggests that it is more likely to be benign. -

Usher syndrome type 2C

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Prof. Karen Avraham, Tel Aviv University

Dec 25, 2024

The ADGRV1 c.16640G>A:p.(Arg5547His) rare, possibly deleterioos variant, was detected in an individual with sloping normal-to-severe HL, that also carried two CDH23 VUSs, c.9629T>C:p.(Ile3210Thr) and c.7849G>C:p.(Gly2617Arg), suggesting digenic inheritance of ADGRV1/CDH23. -

Meniere disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Jun 21, 2021

Digenic inheritance along with NM_000260.4:c.2617C>T(MYO7A) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.084

T;T;.

Eigen

Benign

-0.032

Eigen_PC

Benign

0.024

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.79

.;T;T

M_CAP

Benign

0.0089

MetaRNN

Benign

0.094

T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.0

.;N;.

REVEL

Benign

0.18

Sift

Benign

0.16

.;T;.

Sift4G

Benign

0.20

.;T;.

Polyphen

0.18

B;B;.

Vest4

0.23

MVP

0.52

MPC

0.29

ClinPred

0.019

GERP RS

6.2

Varity_R

0.10

gMVP

0.37

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

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