rs199499672

Positions:

chr5-90720954-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000405460.9(ADGRV1):c.9643G>A(p.Glu3215Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000306 in 1,610,604 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

ADGRV1
ENST00000405460.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 5.87

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:

LOC105379077 (HGNC:):

LOC105379077 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2791213).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.9643G>A	p.Glu3215Lys	missense_variant	45/90	ENST00000405460.9	NP_115495.3
LOC105379077	XR_001742802.2 linkuse as main transcript	n.364-5145C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.9643G>A	p.Glu3215Lys	missense_variant	45/90	1	NM_032119.4	ENSP00000384582	P1	Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.000960

GnomAD3 exomes

AF:

0.000290

AC:

AN:

248528

Hom.:

AF XY:

0.000311

AC XY:

AN XY:

134846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000460

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000443

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000315

AC:

459

AN:

1458406

Hom.:

Cov.:

AF XY:

0.000328

AC XY:

238

AN XY:

725554

show subpopulations

Gnomad4 AFR exome

AF:

0.0000899

Gnomad4 AMR exome

AF:

0.000247

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000454

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.000350

Gnomad4 OTH exome

AF:

0.000216

GnomAD4 genome

AF:

0.000223

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000327

Hom.:

Bravo

AF:

0.000223

ExAC

AF:

0.000348

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2024	Identified in the heterozygous state in a patient with epilepsy and cardiac conduction disorder in published literature (PMID: 29261713); Identified as a single heterozygous variant in a patient with panuveitis in published literature (PMID: 32707200); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29261713, 32707200) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 20, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 25, 2018

The p.Glu3215Lys variant in ADGRV1 has been previously reported by our laborator y in 2 individuals with hearing loss, one of whom also harbored a second ADGRV1 variant of uncertain significance (trans/cis not yet determined). The variant wa s also identified in 51/126478 European chromosomes by the Genome Aggregation Da tabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199499672). However, t his frequency is not high enough to rule out a pathogenic role. Computational pr ediction tools and conservation analysis suggest that this variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the p.Glu32215Lys variant is un certain. ACMG/AMP Criteria applied: PP3. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

.;T

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-0.69

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.5

.;D

REVEL

Benign

0.19

Sift

Uncertain

0.017

.;D

Sift4G

Uncertain

0.011

.;D

Polyphen

0.84

P;P

Vest4

0.56

MVP

0.73

MPC

0.072

ClinPred

0.35

GERP RS

5.8

Varity_R

0.46

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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