rs4916684

chr5-90683772-G-A

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.5851G>A(p.Val1951Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 1,613,458 control chromosomes in the GnomAD database, including 364,981 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42168 hom., cov: 30)
  • Exomes 𝑓: 0.66 (322813 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.584

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=8.4812325E-7).
• BP6: Variant 5-90683772-G-A is Benign according to our data. Variant chr5-90683772-G-A is described in ClinVar as [Benign]. Clinvar id is 46343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90683772-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.5851G>A	p.Val1951Ile	missense_variant	28/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.5851G>A	p.Val1951Ile	missense_variant	28/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.735 AC: 111694 AN: 151874 Hom.: 42094 Cov.: 30

Gnomad AFR AF: 0.897

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.773

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.812

Gnomad SAS AF: 0.726

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.743

GnomAD3 exomes AF: 0.710 AC: 176347 AN: 248522 Hom.: 63398 AF XY: 0.701 AC XY: 94452 AN XY: 134798

Gnomad AFR exome AF: 0.903

Gnomad AMR exome AF: 0.825

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.801

Gnomad SAS exome AF: 0.722

Gnomad FIN exome AF: 0.668

Gnomad NFE exome AF: 0.642

Gnomad OTH exome AF: 0.701

GnomAD4 exome AF: 0.662 AC: 966891 AN: 1461466 Hom.: 322813 Cov.: 55 AF XY: 0.661 AC XY: 480768 AN XY: 727024

Gnomad4 AFR exome AF: 0.903

Gnomad4 AMR exome AF: 0.821

Gnomad4 ASJ exome AF: 0.666

Gnomad4 EAS exome AF: 0.818

Gnomad4 SAS exome AF: 0.720

Gnomad4 FIN exome AF: 0.667

Gnomad4 NFE exome AF: 0.636

Gnomad4 OTH exome AF: 0.687

GnomAD4 genome AF: 0.736 AC: 111822 AN: 151992 Hom.: 42168 Cov.: 30 AF XY: 0.738 AC XY: 54801 AN XY: 74268

Gnomad4 AFR AF: 0.897

Gnomad4 AMR AF: 0.773

Gnomad4 ASJ AF: 0.669

Gnomad4 EAS AF: 0.813

Gnomad4 SAS AF: 0.724

Gnomad4 FIN AF: 0.663

Gnomad4 NFE AF: 0.639

Gnomad4 OTH AF: 0.747

Alfa AF: 0.668 Hom.: 71762

Bravo AF: 0.755

TwinsUK AF: 0.629 AC: 2334

ALSPAC AF: 0.649 AC: 2500

ESP6500AA AF: 0.906 AC: 3480

ESP6500EA AF: 0.645 AC: 5339

ExAC AF: 0.707 AC: 85425

Asia WGS AF: 0.808 AC: 2808 AN: 3478

EpiCase AF: 0.651

EpiControl AF: 0.649

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 23, 2010	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 26, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Usher syndrome type 2C Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.7
Dann	Benign	0.18
DEOGEN2	Benign	0.043	T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.052	N
MetaRNN	Benign	8.5e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.50	T
Polyphen		0.0	B;B;.
Vest4		0.028
MPC		0.042
ClinPred		0.00070	T
GERP RS		3.2
Varity_R		0.032
gMVP		0.20

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: rs4916684; hg19: chr5-89979589; COSMIC: COSV67980016;