chr5-90652488-A-G

Position:

chr5-90652488-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000405460.9(ADGRV1):c.3559A>G(p.Ile1187Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,613,458 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0091 ( 25 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 27 hom. )

Consequence

ADGRV1
ENST00000405460.9 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.691

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029987395).

BP6

Variant 5-90652488-A-G is Benign according to our data. Variant chr5-90652488-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 46319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90652488-A-G is described in Lovd as [Benign]. Variant chr5-90652488-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00913 (1391/152296) while in subpopulation AFR AF= 0.0311 (1290/41544). AF 95% confidence interval is 0.0296. There are 25 homozygotes in gnomad4. There are 673 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 25 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.3559A>G	p.Ile1187Val	missense_variant	19/90	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.3559A>G	p.Ile1187Val	missense_variant	19/90	1	NM_032119.4	ENSP00000384582	P1	Q8WXG9-1
ADGRV1	ENST00000640403.1 linkuse as main transcript	c.862A>G	p.Ile288Val	missense_variant	9/29	5		ENSP00000492531
ADGRV1	ENST00000504142.2 linkuse as main transcript	n.2325A>G		non_coding_transcript_exon_variant	13/14	5
ADGRV1	ENST00000639676.1 linkuse as main transcript	n.1157A>G		non_coding_transcript_exon_variant	7/11	5

Frequencies

GnomAD3 genomes

AF:

0.00915

AC:

1392

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0311

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00252

AC:

626

AN:

248896

Hom.:

AF XY:

0.00195

AC XY:

263

AN XY:

135022

show subpopulations

Gnomad AFR exome

AF:

0.0307

Gnomad AMR exome

AF:

0.00250

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000293

Gnomad OTH exome

AF:

0.00166

GnomAD4 exome

AF:

0.00112

AC:

1643

AN:

1461162

Hom.:

Cov.:

AF XY:

0.000962

AC XY:

699

AN XY:

726842

show subpopulations

Gnomad4 AFR exome

AF:

0.0331

Gnomad4 AMR exome

AF:

0.00248

Gnomad4 ASJ exome

AF:

0.00168

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000173

Gnomad4 OTH exome

AF:

0.00257

GnomAD4 genome

AF:

0.00913

AC:

1391

AN:

152296

Hom.:

Cov.:

AF XY:

0.00903

AC XY:

673

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0311

Gnomad4 AMR

AF:

0.00444

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00185

Hom.:

Bravo

AF:

0.0108

ESP6500AA

AF:

0.0286

AC:

108

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.00300

AC:

362

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000219

EpiControl

AF:

0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 26, 2012	p.Ile1187Val in exon 19 of GPR98: This variant is not expected to have clinical significance because it has been identified in 3% (93/3088) of African American chromosomes in a broad population by the NHLBI Exome sequencing project (http:// evs.gs.washington.edu/EVS/; dbSNP rs16868935). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2017	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	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:5

Likely benign, 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	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -

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

0.066

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

9.0

DANN

Benign

0.40

DEOGEN2

Benign

0.054

T;T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.69

.;T;T

MetaRNN

Benign

0.0030

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.48

.;N;.

REVEL

Benign

0.12

Sift

Benign

0.39

.;T;.

Sift4G

Benign

0.30

.;T;.

Polyphen

0.0010

B;B;.

Vest4

0.073

MVP

0.24

MPC

0.059

ClinPred

0.0029

GERP RS

-7.0

Varity_R

0.025

gMVP

0.38

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