rs148097083

Positions:

chr5-90647764-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_032119.4(ADGRV1):c.3289G>A(p.Gly1097Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00309 in 1,609,230 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0047 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 33 hom. )

Consequence

ADGRV1
NM_032119.4 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

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

Conservation

PhyloP100: 9.64

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 Likely_benign. Variant got -4 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: Cadd, dbscSNV1_ADA, dbscSNV1_RF, Eigen, FATHMM_MKL, M_CAP, phyloP100way_vertebrate [when AlphaMissense, BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP6

Variant 5-90647764-G-A is Benign according to our data. Variant chr5-90647764-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158651.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=4}. Variant chr5-90647764-G-A is described in Lovd as [Likely_benign]. Variant chr5-90647764-G-A is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 8 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.3289G>A	p.Gly1097Ser	missense_variant, splice_region_variant	17/90	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.3289G>A	p.Gly1097Ser	missense_variant, splice_region_variant	17/90	1	NM_032119.4	ENSP00000384582.2	Q8WXG9-1
ADGRV1	ENST00000640403.1 linkuse as main transcript	c.592G>A	p.Gly198Ser	missense_variant, splice_region_variant	7/29	5		ENSP00000492531.1	A0A1W2PRC7
ADGRV1	ENST00000504142.2 linkuse as main transcript	n.2055G>A		splice_region_variant, non_coding_transcript_exon_variant	11/14	5
ADGRV1	ENST00000639676.1 linkuse as main transcript	n.887G>A		splice_region_variant, non_coding_transcript_exon_variant	5/11	5

Frequencies

GnomAD3 genomes

AF:

0.00471

AC:

717

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0344

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00344

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00521

AC:

1284

AN:

246676

Hom.:

AF XY:

0.00515

AC XY:

689

AN XY:

133914

show subpopulations

Gnomad AFR exome

AF:

0.0000648

Gnomad AMR exome

AF:

0.00140

Gnomad ASJ exome

AF:

0.00943

Gnomad EAS exome

AF:

0.0000558

Gnomad SAS exome

AF:

0.000991

Gnomad FIN exome

AF:

0.0341

Gnomad NFE exome

AF:

0.00325

Gnomad OTH exome

AF:

0.00569

GnomAD4 exome

AF:

0.00292

AC:

4260

AN:

1456984

Hom.:

Cov.:

AF XY:

0.00296

AC XY:

2141

AN XY:

724414

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.00180

Gnomad4 ASJ exome

AF:

0.00930

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000687

Gnomad4 FIN exome

AF:

0.0295

Gnomad4 NFE exome

AF:

0.00189

Gnomad4 OTH exome

AF:

0.00311

GnomAD4 genome

AF:

0.00471

AC:

717

AN:

152246

Hom.:

Cov.:

AF XY:

0.00625

AC XY:

465

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0344

Gnomad4 NFE

AF:

0.00344

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00315

Hom.:

Bravo

AF:

0.00210

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000273

AC:

ESP6500EA

AF:

0.00343

AC:

ExAC

AF:

0.00442

AC:

534

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00316

EpiControl

AF:

0.00279

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ADGRV1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Gly1097Ser in Exon 17 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (21/6558) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs148097083). -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;T;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.0095

T;T;T

MetaSVM

Benign

-0.30

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.9

.;D;.

REVEL

Uncertain

0.53

Sift

Uncertain

0.0070

.;D;.

Sift4G

Uncertain

0.017

.;D;.

Polyphen

1.0

D;D;.

Vest4

0.75

MVP

0.74

MPC

0.30

ClinPred

0.045

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.49

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.89

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