rs375632680

Positions:

chr5-90763312-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_032119.4(ADGRV1):c.12128T>C(p.Ile4043Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000136 in 1,563,534 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 6.23

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 Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18300104).

BP6

Variant 5-90763312-T-C is Benign according to our data. Variant chr5-90763312-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228706.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.12128T>C	p.Ile4043Thr	missense_variant	59/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.12128T>C	p.Ile4043Thr	missense_variant	59/90	1	NM_032119.4	P1	Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000803

AC:

AN:

236524

Hom.:

AF XY:

0.0000858

AC XY:

AN XY:

128176

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000175

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000140

AC:

198

AN:

1411462

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

695268

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000181

Gnomad4 OTH exome

AF:

0.0000517

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000367

AC:

ExAC

AF:

0.0000828

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 24, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Usher syndrome type 2C

Uncertain:1

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;C2931213:Usher syndrome type 2C

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 15, 2018

The p.Ile4043Thr variant in ADGRV1 has been previously reported by our laborator y in the heterozygous state in 3 individuals with hearing loss, but a variant af fecting the remaining copy of the gene was not identified. This variant has been identified in 21/122272 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs375632680). Computational p rediction tools and conservation analysis suggest that the p.Ile4043Thr variant may not impact the protein with the site poorly conserved. Also, this gene is hi ghly polymorphic with very few pathogenic missense variants. In summary, this va riant meets criteria to be classified as likely benign. ACMG/AMP Criteria applie d: PM2_Supporting, BP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.080

T;T;.

Eigen

Benign

0.069

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.74

.;T;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.79

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.3

.;N;.

REVEL

Benign

0.11

Sift

Benign

0.089

.;T;.

Sift4G

Uncertain

0.0040

.;D;.

Polyphen

0.18

B;B;.

Vest4

0.37

MVP

0.58

MPC

0.058

ClinPred

0.15

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.16

gMVP

0.71

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