5-90791344-C-G

Position:

chr5-90791344-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_032119.4(ADGRV1):c.14515C>G(p.Gln4839Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00174 in 1,547,346 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q4839H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0022 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 51 hom. )

Consequence

ADGRV1
NM_032119.4 missense, splice_region

Scores

Splicing: ADA: 0.9848

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.94

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 -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-90791346-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438169.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.008897245).

BP6

Variant 5-90791344-C-G is Benign according to our data. Variant chr5-90791344-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 46271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90791344-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0022 (335/152272) while in subpopulation EAS AF= 0.0294 (152/5170). AF 95% confidence interval is 0.0256. There are 4 homozygotes in gnomad4. There are 197 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.14515C>G	p.Gln4839Glu	missense_variant, splice_region_variant	70/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.14515C>G	p.Gln4839Glu	missense_variant, splice_region_variant	70/90	1	NM_032119.4	P1	Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.00220

AC:

335

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0293

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0119

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00324

AC:

514

AN:

158756

Hom.:

AF XY:

0.00313

AC XY:

260

AN XY:

83120

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0226

Gnomad SAS exome

AF:

0.000612

Gnomad FIN exome

AF:

0.0112

Gnomad NFE exome

AF:

0.000298

Gnomad OTH exome

AF:

0.00135

GnomAD4 exome

AF:

0.00169

AC:

2362

AN:

1395074

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

1127

AN XY:

687704

show subpopulations

Gnomad4 AFR exome

AF:

0.0000315

Gnomad4 AMR exome

AF:

0.00117

Gnomad4 ASJ exome

AF:

0.0000406

Gnomad4 EAS exome

AF:

0.0381

Gnomad4 SAS exome

AF:

0.000716

Gnomad4 FIN exome

AF:

0.0104

Gnomad4 NFE exome

AF:

0.000256

Gnomad4 OTH exome

AF:

0.00155

GnomAD4 genome

AF:

0.00220

AC:

335

AN:

152272

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

197

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0294

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0119

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00123

Hom.:

Bravo

AF:

0.00134

ExAC

AF:

0.00193

AC:

219

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	This variant is associated with the following publications: (PMID: 26969326) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Gln4839Glu in Exon 70 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 4.2% (5/120) of chromosomes from a population in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs79 464236). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 27, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -

Usher syndrome type 2C

Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;T;.;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.74

.;T;T;T;T

MetaRNN

Benign

0.0064

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.4

.;N;.;.;.

REVEL

Benign

0.19

Sift

Pathogenic

0.0

.;D;.;.;.

Sift4G

Pathogenic

0.0

.;D;.;.;.

Polyphen

1.0

D;D;.;.;.

Vest4

0.54

MVP

0.69

MPC

0.084

ClinPred

0.070

GERP RS

5.8

Varity_R

0.45

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Benign

0.67

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