rs200792658

Positions:

• chr5-90716722-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032119.4(ADGRV1):​c.9440G>A​(p.Arg3147Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,610,666 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Synonymous variant affecting the same amino acid position (i.e. R3147R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5 B:1
• Conservation: PhyloP100: 3.25

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]

LOC105379077 (HGNC:):

ACMG classification

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=0.025375962).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.9440G>A	p.Arg3147Gln	missense_variant	43/90	ENST00000405460.9
LOC105379077	XR_001742802.2	n.364-913C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.9440G>A	p.Arg3147Gln	missense_variant	43/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000302 AC: 75 AN: 248466 Hom.: 0 AF XY: 0.000297 AC XY: 40 AN XY: 134858

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00122

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: 0.000160

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000218 AC: 318 AN: 1458406 Hom.: 0 Cov.: 29 AF XY: 0.000219 AC XY: 159 AN XY: 725606

Gnomad4 AFR exome AF: 0.000599

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000197

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74442

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000140 Hom.: 1

Bravo AF: 0.000518

ESP6500AA AF: 0.000551 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000199 AC: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 24, 2017	- -

Usher syndrome type 2 Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Idiopathic generalized epilepsy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Paris Brain Institute, Inserm - ICM

-

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 04, 2020

The p.Arg3147Gln variant in ADGRV1 (also known as GPR98) has been previously reported in 5 individuals with hearing loss (Neveling 2013, LMM data), 4 of whom also carried the p.Gly573Val variant of uncertain significance in ADGRV1. These two variants were determined to be in cis in 1 individual tested at our laboratory. The p.Arg3147Gln variant has also been reported in ClinVar (Variation ID # 46404) as of uncertain significance. It has also been identified in 0.1% (42/35316) of Latino chromosomes at a similar frequency as the p.Gly573Val variant (0.1%; 41/35348 Latino chromosomes) by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200792658 and dbSNP rs200789563). Collectively, these data suggest that these variants are in linkage disequilibrium and are in cis in all reported individuals identified thus far. Moreover, arginine (Arg) at position 3147 is not conserved in mammals or evolutionarily distant species. Of note, 2 mammals (Elephant and Opossum) carry a glutamine (Gln) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg3147Gln variant is uncertain. ACMG/AMP criteria applied: BS1_Supporting, BP4. -

Febrile seizures, familial, 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Institute of Human Genetics, University Hospital of Duesseldorf

-

- -

Usher syndrome type 2C Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.016
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.025	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.29	T
Polyphen		0.090	B;B
Vest4		0.14
MVP		0.41
MPC		0.26
ClinPred		0.034	T
GERP RS		3.2
Varity_R		0.23
gMVP		0.61

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

Other links and lift over

dbSNP: rs200792658; hg19: chr5-90012539; COSMIC: COSV67990404; COSMIC: COSV67990404;