rs758506587

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_ModerateBP6_Very_Strong

The NM_032119.4(ADGRV1):c.11999C>T(p.Thr4000Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,602,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T4000T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0470

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 -8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.111368746).

BP6

Variant 5-90759467-C-T is Benign according to our data. Variant chr5-90759467-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 517311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.11999C>T	p.Thr4000Met	missense_variant	58/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.11999C>T	p.Thr4000Met	missense_variant	58/90	1	NM_032119.4	P1	Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000258

AC:

AN:

232306

Hom.:

AF XY:

0.00000800

AC XY:

AN XY:

125068

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000179

Gnomad SAS exome

AF:

0.0000352

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000193

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1450372

Hom.:

Cov.:

AF XY:

0.00000833

AC XY:

AN XY:

720092

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000233

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000109

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000494

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 20, 2017

p.Thr4000Met in exon 58 of GPR98: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, more than 10 mammals (including gibbon, elephant, and cape elephant shrew ) have a methionine (Met) at this position despite high nearby amino acid conser vation. In addition, computational prediction tools do not suggest a high likeli hood of impact to the protein. It has been identified in 3/16124 of East Asian c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs758506587). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.52

Cadd

Benign

1.3

Dann

Benign

0.54

DEOGEN2

Benign

0.12

T;T;.

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.035

M_CAP

Benign

0.042

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

Polyphen

0.17

B;B;.

Vest4

0.10

MVP

0.17

MPC

0.061

ClinPred

0.023

GERP RS

-5.0

Varity_R

0.014

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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