chr5-90745073-T-C

Position:

chr5-90745073-T-C

Variant summary

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

The NM_032119.4(ADGRV1):c.10577T>C(p.Met3526Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 1,613,534 control chromosomes in the GnomAD database, including 845 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 0.023 ( 63 hom., cov: 32)

Exomes 𝑓: 0.030 ( 782 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -2.04

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=0.0023483634).

BP6

Variant 5-90745073-T-C is Benign according to our data. Variant chr5-90745073-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 46249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90745073-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0227 (3451/152292) while in subpopulation NFE AF= 0.0352 (2395/68002). AF 95% confidence interval is 0.034. There are 63 homozygotes in gnomad4. There are 1656 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 63 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.10577T>C	p.Met3526Thr	missense_variant	51/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.10577T>C	p.Met3526Thr	missense_variant	51/90	1	NM_032119.4	P1	Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.0227

AC:

3451

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00579

Gnomad AMI

AF:

0.0757

Gnomad AMR

AF:

0.0142

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.0338

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0352

Gnomad OTH

AF:

0.0191

GnomAD3 exomes

AF:

0.0231

AC:

5748

AN:

249126

Hom.:

107

AF XY:

0.0232

AC XY:

3130

AN XY:

135138

show subpopulations

Gnomad AFR exome

AF:

0.00484

Gnomad AMR exome

AF:

0.0111

Gnomad ASJ exome

AF:

0.0132

Gnomad EAS exome

AF:

0.00295

Gnomad SAS exome

AF:

0.0146

Gnomad FIN exome

AF:

0.0372

Gnomad NFE exome

AF:

0.0330

Gnomad OTH exome

AF:

0.0222

GnomAD4 exome

AF:

0.0299

AC:

43629

AN:

1461242

Hom.:

782

Cov.:

AF XY:

0.0294

AC XY:

21344

AN XY:

726924

show subpopulations

Gnomad4 AFR exome

AF:

0.00475

Gnomad4 AMR exome

AF:

0.0114

Gnomad4 ASJ exome

AF:

0.0123

Gnomad4 EAS exome

AF:

0.00224

Gnomad4 SAS exome

AF:

0.0157

Gnomad4 FIN exome

AF:

0.0359

Gnomad4 NFE exome

AF:

0.0340

Gnomad4 OTH exome

AF:

0.0239

GnomAD4 genome

AF:

0.0227

AC:

3451

AN:

152292

Hom.:

Cov.:

AF XY:

0.0222

AC XY:

1656

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00577

Gnomad4 AMR

AF:

0.0142

Gnomad4 ASJ

AF:

0.0121

Gnomad4 EAS

AF:

0.00347

Gnomad4 SAS

AF:

0.0145

Gnomad4 FIN

AF:

0.0338

Gnomad4 NFE

AF:

0.0352

Gnomad4 OTH

AF:

0.0189

Alfa

AF:

0.0296

Hom.:

119

Bravo

AF:

0.0197

TwinsUK

AF:

0.0305

AC:

113

ALSPAC

AF:

0.0376

AC:

145

ESP6500AA

AF:

0.00476

AC:

ESP6500EA

AF:

0.0304

AC:

250

ExAC

AF:

0.0232

AC:

2799

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0297

EpiControl

AF:

0.0277

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2013	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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2014	- -

not provided

Benign:3Other:1

not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 26, 2018	- -

Usher syndrome type 2C

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

0.061

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.046

DANN

Benign

0.34

DEOGEN2

Benign

0.063

T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.25

.;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.090

.;N

REVEL

Benign

0.045

Sift

Benign

0.57

.;T

Sift4G

Benign

0.57

.;T

Polyphen

0.0050

B;B

Vest4

0.028

MPC

0.053

ClinPred

0.0018

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.048

gMVP

0.30

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