rs370906851

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032119.4(ADGRV1):c.16331C>A(p.Thr5444Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T5444A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 0 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 1.58

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0446963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.16331C>A	p.Thr5444Lys	missense_variant	76/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.16331C>A	p.Thr5444Lys	missense_variant	76/90	1	NM_032119.4	P1	Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000337

AC:

AN:

249132

Hom.:

AF XY:

0.000281

AC XY:

AN XY:

135158

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.000646

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000545

AC:

797

AN:

1461536

Hom.:

Cov.:

AF XY:

0.000536

AC XY:

390

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000677

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.000368

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000716

Hom.:

Bravo

AF:

0.000385

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000243

AC:

ExAC

AF:

0.000306

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 03, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 29, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 28, 2022

Variant summary: ADGRV1 c.16331C>A (p.Thr5444Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 249132 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in ADGRV1 causing Usher Syndrome (0.00034 vs 0.0054), allowing no conclusion about variant significance. c.16331C>A has been reported in the literature in individuals affected with Usher Syndrome/deafness with non-informative genotypes (pathogenicity of the second allele uncertain) (examples: Sloan-Heggen_2016 and Zhou_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

ADGRV1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 2023

The ADGRV1 c.16331C>A variant is predicted to result in the amino acid substitution p.Thr5444Lys. This variant was reported in the heterozygous state along with a second potentially causative variant (p.Ile508Leu) in an individual with hearing loss (Table S3, Sloan-Heggen. 2016. PubMed ID: 26969326). This variant is reported in 0.065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

0.15

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.15

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Benign

0.22

T;T;.

Eigen

Benign

0.068

Eigen_PC

Benign

0.066

FATHMM_MKL

Benign

0.42

M_CAP

Benign

0.013

MetaRNN

Benign

0.045

T;T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

0.97

D;N

PrimateAI

Benign

0.45

Polyphen

0.91

P;P;.

Vest4

0.66

MVP

0.60

MPC

0.056

ClinPred

0.10

GERP RS

4.4

Varity_R

0.30

gMVP

0.57

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