rs201733037

Positions:

chr5-90694338-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_032119.4(ADGRV1):c.7582C>T(p.Pro2528Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,613,972 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0037 ( 23 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.80

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0103443265).

BP6

Variant 5-90694338-C-T is Benign according to our data. Variant chr5-90694338-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46377.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=5, Uncertain_significance=1}. Variant chr5-90694338-C-T is described in Lovd as [Benign]. Variant chr5-90694338-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00273 (416/152322) while in subpopulation SAS AF= 0.0166 (80/4832). AF 95% confidence interval is 0.0136. There are 4 homozygotes in gnomad4. There are 223 alleles in male gnomad4 subpopulation. Median coverage is 33. 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	Protein	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.7582C>T	p.Pro2528Ser	missense_variant	33/90	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.7582C>T	p.Pro2528Ser	missense_variant	33/90	1	NM_032119.4	ENSP00000384582	P1	Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.00273

AC:

415

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0165

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00391

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00417

AC:

1038

AN:

249054

Hom.:

AF XY:

0.00484

AC XY:

654

AN XY:

135104

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.00226

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0146

Gnomad FIN exome

AF:

0.000696

Gnomad NFE exome

AF:

0.00412

Gnomad OTH exome

AF:

0.00396

GnomAD4 exome

AF:

0.00368

AC:

5373

AN:

1461650

Hom.:

Cov.:

AF XY:

0.00404

AC XY:

2935

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00239

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0156

Gnomad4 FIN exome

AF:

0.00103

Gnomad4 NFE exome

AF:

0.00321

Gnomad4 OTH exome

AF:

0.00364

GnomAD4 genome

AF:

0.00273

AC:

416

AN:

152322

Hom.:

Cov.:

AF XY:

0.00299

AC XY:

223

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0166

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00392

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00300

Hom.:

Bravo

AF:

0.00217

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00362

AC:

ExAC

AF:

0.00430

AC:

520

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.00354

EpiControl

AF:

0.00421

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2019	This variant is associated with the following publications: (PMID: 26576034) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 28, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	ADGRV1: BP4, BS1, BS2 -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 29, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Pro2528Ser in exon 33 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (27/6698) of European American chromosomes and 0.09% (3/3162) of African American chromosomes from a broad pop ulation by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/ ). -

Meniere disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Jun 21, 2021

Digenic inheritance along with NM_000260.4:c.2507G>A(MYO7A) -

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

0.19

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.096

T;T;.

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.92

.;D;D

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.99

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.1

.;N;.

REVEL

Benign

0.096

Sift

Benign

0.11

.;T;.

Sift4G

Benign

0.14

.;T;.

Polyphen

0.51

P;P;.

Vest4

0.20

MVP

0.64

MPC

0.13

ClinPred

0.012

GERP RS

5.9

Varity_R

0.15

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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