5-90692647-A-T

Position:

chr5-90692647-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_032119.4(ADGRV1):c.6994A>T(p.Ile2332Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,611,626 control chromosomes in the GnomAD database, including 1 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 0.00052 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:5

Conservation

PhyloP100: 0.390

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:

ADGRV1 (HGNC:):

ADGRV1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.021339357).

BP6

Variant 5-90692647-A-T is Benign according to our data. Variant chr5-90692647-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46359.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5, Benign=2}. Variant chr5-90692647-A-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.6994A>T	p.Ile2332Phe	missense_variant	32/90	ENST00000405460.9	NP_115495.3	Q8WXG9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.6994A>T	p.Ile2332Phe	missense_variant	32/90	1	NM_032119.4	ENSP00000384582.2		Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.000281

AC:

AN:

245420

Hom.:

AF XY:

0.000278

AC XY:

AN XY:

133156

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.000238

Gnomad ASJ exome

AF:

0.00271

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000242

Gnomad OTH exome

AF:

0.000846

GnomAD4 exome

AF:

0.000254

AC:

370

AN:

1459384

Hom.:

Cov.:

AF XY:

0.000266

AC XY:

193

AN XY:

725822

show subpopulations

Gnomad4 AFR exome

AF:

0.000509

Gnomad4 AMR exome

AF:

0.000609

Gnomad4 ASJ exome

AF:

0.00330

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000467

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000161

Gnomad4 OTH exome

AF:

0.000680

GnomAD4 genome

AF:

0.000519

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.000372

Hom.:

Bravo

AF:

0.000620

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000244

AC:

ExAC

AF:

0.000207

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 11, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2020	This variant is associated with the following publications: (PMID: 26969326) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 29, 2017	The ADGRV1 p.Ile2332Phe variant (rs193030567) was reported in one individual with a diagnosis of Usher syndrome type 2C who also harbored the p.Val617Met variant (Sloan-Heggen 2016). The p.Ile2332Phe variant is listed in the Genome Aggregation Database (gnomAD) with an allele frequency of 0.3 percent in the Ashkenazi Jewish population (identified on 28 out of 10,072 chromosomes) and has been reported to the ClinVar database (Variation ID: 46359). The isoleucine at position 2332 is highly conserved considering 12 species up to zebrafish (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the ADGRV1 protein (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Ile2332Phe variant with certainty. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Usher syndrome type 2C

Uncertain:2Benign: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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Uncertain significance, criteria provided, single submitter	research	DECIPHERD-UDD, Universidad del Desarrollo	Jul 01, 2023	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 25, 2017

p.Ile2332Phe in exon 32 of GPR98: This variant is not expected to have clinical significance because it has been identified in 0.3% (28/10072) of Ashkenazi Jewi sh chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org; dbSNP rs193030567). -

ADGRV1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;T;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.77

.;T;T

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Benign

-0.99

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.9

.;D;.

REVEL

Benign

0.23

Sift

Uncertain

0.0040

.;D;.

Sift4G

Uncertain

0.0060

.;D;.

Polyphen

0.95

P;P;.

Vest4

0.84

MVP

0.64

MPC

0.36

ClinPred

0.28

GERP RS

3.4

Varity_R

0.48

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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