rs2460169

chr5-90777969-G-Achr5-90777969-G-Cchr5-90777969-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032119.4(ADGRV1):c.12592G>A(p.Val4198Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 1,610,530 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V4198L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.018 (59 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (76 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.822

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001982808).
• BP6: Variant 5-90777969-G-A is Benign according to our data. Variant chr5-90777969-G-A is described in ClinVar as [Benign]. Clinvar id is 46262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90777969-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.12592G>A	p.Val4198Met	missense_variant	62/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.12592G>A	p.Val4198Met	missense_variant	62/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2675 AN: 152114 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.0597

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00858

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00468 AC: 1142 AN: 243834 Hom.: 29 AF XY: 0.00348 AC XY: 460 AN XY: 132028

Gnomad AFR exome AF: 0.0614

Gnomad AMR exome AF: 0.00339

Gnomad ASJ exome AF: 0.000507

Gnomad EAS exome AF: 0.000170

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.000525

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00203 AC: 2957 AN: 1458298 Hom.: 76 Cov.: 31 AF XY: 0.00175 AC XY: 1269 AN XY: 725040

Gnomad4 AFR exome AF: 0.0607

Gnomad4 AMR exome AF: 0.00343

Gnomad4 ASJ exome AF: 0.000500

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.000263

Gnomad4 NFE exome AF: 0.000417

Gnomad4 OTH exome AF: 0.00415

GnomAD4 genome AF: 0.0176 AC: 2678 AN: 152232 Hom.: 59 Cov.: 32 AF XY: 0.0168 AC XY: 1253 AN XY: 74428

Gnomad4 AFR AF: 0.0596

Gnomad4 AMR AF: 0.00857

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00308 Hom.: 9

Bravo AF: 0.0196

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0553 AC: 210

ESP6500EA AF: 0.00109 AC: 9

ExAC AF: 0.00545 AC: 658

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Val4198Met in Exon 62 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 5.4% (168/3106) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs2460169). -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Usher syndrome type 2C Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.076
Dann	Benign	0.78
DEOGEN2	Benign	0.098	T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.036	N
MetaRNN	Benign	0.0020	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
Polyphen		0.042	B;B;.
Vest4		0.15
MVP		0.12
MPC		0.048
ClinPred		0.0014	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.34

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: rs2460169; hg19: chr5-90073786;