rs41308846

Positions:

chr5-90684054-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_032119.4(ADGRV1):c.6133G>A(p.Gly2045Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00628 in 1,613,882 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0046 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 48 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:13

Conservation

PhyloP100: 9.69

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 -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Dann, Eigen, FATHMM_MKL, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.011430383).

BP6

Variant 5-90684054-G-A is Benign according to our data. Variant chr5-90684054-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46348.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=7}. Variant chr5-90684054-G-A is described in Lovd as [Benign]. Variant chr5-90684054-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00461 (702/152222) while in subpopulation NFE AF= 0.00816 (555/68000). AF 95% confidence interval is 0.0076. There are 2 homozygotes in gnomad4. There are 325 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.6133G>A	p.Gly2045Arg	missense_variant	28/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.6133G>A	p.Gly2045Arg	missense_variant	28/90	1	NM_032119.4	P1	Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.00462

AC:

702

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00415

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00816

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00426

AC:

1058

AN:

248490

Hom.:

AF XY:

0.00425

AC XY:

573

AN XY:

134858

show subpopulations

Gnomad AFR exome

AF:

0.000775

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.00448

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000752

Gnomad FIN exome

AF:

0.00362

Gnomad NFE exome

AF:

0.00725

Gnomad OTH exome

AF:

0.00315

GnomAD4 exome

AF:

0.00646

AC:

9441

AN:

1461660

Hom.:

Cov.:

AF XY:

0.00631

AC XY:

4585

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.000896

Gnomad4 AMR exome

AF:

0.00197

Gnomad4 ASJ exome

AF:

0.00413

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000684

Gnomad4 FIN exome

AF:

0.00451

Gnomad4 NFE exome

AF:

0.00772

Gnomad4 OTH exome

AF:

0.00533

GnomAD4 genome

AF:

0.00461

AC:

702

AN:

152222

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

325

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00275

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00415

Gnomad4 NFE

AF:

0.00816

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00718

Hom.:

Bravo

AF:

0.00430

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.000273

AC:

ESP6500EA

AF:

0.00797

AC:

ExAC

AF:

0.00439

AC:

530

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00725

EpiControl

AF:

0.00634

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:8

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	Mar 01, 2024	ADGRV1: BS1, BS2 -
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	Mar 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2020	This variant is associated with the following publications: (PMID: 24498627, 30245029, 32707200) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 31, 2017	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 02, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 14, 2015	p.Gly2045Arg in exon 28 of GPR98: This variant is not expected to have clinical significance because it has been identified in 0.7% (480/67628) of European chro mosomes by the Exome Aggregation Consortium, including one homozygote (ExAC, htt p://exac.broadinstitute.org; dbSNP rs41308846). -

Usher syndrome type 2C

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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. -

Febrile seizures, familial, 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 03, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

T;T;.

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.84

.;T;T

M_CAP

Pathogenic

0.55

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.34

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-4.4

.;D;.

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0030

.;D;.

Sift4G

Uncertain

0.0050

.;D;.

Polyphen

1.0

D;D;.

Vest4

0.90

MutPred

0.79

Loss of glycosylation at S2044 (P = 0.0283);Loss of glycosylation at S2044 (P = 0.0283);.;

MVP

0.75

MPC

0.35

ClinPred

0.034

GERP RS

5.7

Varity_R

0.74

gMVP

0.76

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