5-90840983-A-G

Position:

chr5-90840983-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_032119.4(ADGRV1):c.17017A>G(p.Lys5673Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00424 in 1,390,998 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 17 hom. )

Consequence

ADGRV1
NM_032119.4 missense, splice_region

Scores

Splicing: ADA: 0.0007120

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 4.00

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0072719157).

BP6

Variant 5-90840983-A-G is Benign according to our data. Variant chr5-90840983-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46288.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=3, Uncertain_significance=1}. Variant chr5-90840983-A-G is described in Lovd as [Benign]. Variant chr5-90840983-A-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 17 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.17017A>G	p.Lys5673Glu	missense_variant, splice_region_variant	78/90	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.17017A>G	p.Lys5673Glu	missense_variant, splice_region_variant	78/90	1	NM_032119.4	ENSP00000384582	P1	Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

381

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00410

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00366

AC:

541

AN:

147990

Hom.:

AF XY:

0.00359

AC XY:

284

AN XY:

79154

show subpopulations

Gnomad AFR exome

AF:

0.000649

Gnomad AMR exome

AF:

0.000653

Gnomad ASJ exome

AF:

0.000684

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000537

Gnomad FIN exome

AF:

0.00242

Gnomad NFE exome

AF:

0.00605

Gnomad OTH exome

AF:

0.00369

GnomAD4 exome

AF:

0.00445

AC:

5516

AN:

1238668

Hom.:

Cov.:

AF XY:

0.00446

AC XY:

2664

AN XY:

597042

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.000700

Gnomad4 ASJ exome

AF:

0.000350

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000437

Gnomad4 FIN exome

AF:

0.00334

Gnomad4 NFE exome

AF:

0.00514

Gnomad4 OTH exome

AF:

0.00347

GnomAD4 genome

AF:

0.00251

AC:

382

AN:

152330

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

170

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00273

Gnomad4 NFE

AF:

0.00410

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00311

Hom.:

Bravo

AF:

0.00260

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.000803

AC:

ESP6500EA

AF:

0.00402

AC:

ExAC

AF:

0.00374

AC:

434

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:7

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 13, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ADGRV1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2018	This variant is associated with the following publications: (PMID: 32707200) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 31, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Lys5673Glu in Exon 78 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (25/6622) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs41303350). -
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. -

ADGRV1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2019

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

0.14

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.19

T;T;.

Eigen

Benign

-0.054

Eigen_PC

Benign

-0.0082

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.74

.;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.0073

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.92

D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.5

.;N;.

REVEL

Benign

0.13

Sift

Uncertain

0.0070

.;D;.

Sift4G

Uncertain

0.0080

.;D;.

Polyphen

0.75

P;P;.

Vest4

0.51

MVP

0.51

MPC

0.061

ClinPred

0.030

GERP RS

4.6

Varity_R

0.35

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00071

dbscSNV1_RF

Benign

0.010

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