rs2438378

chr5-90823507-G-Achr5-90823507-G-Cchr5-90823507-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.16279G>A(p.Val5427Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 1,613,940 control chromosomes in the GnomAD database, including 798,880 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. V5427E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.97 (72243 hom., cov: 32)
  • Exomes 𝑓: 1.0 (726637 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.120

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=6.644323E-7).
• BP6: Variant 5-90823507-G-A is Benign according to our data. Variant chr5-90823507-G-A is described in ClinVar as [Benign]. Clinvar id is 46285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90823507-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.16279G>A	p.Val5427Met	missense_variant	76/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.16279G>A	p.Val5427Met	missense_variant	76/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.973 AC: 148114 AN: 152156 Hom.: 72197 Cov.: 32

Gnomad AFR AF: 0.911

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.986

Gnomad ASJ AF: 0.995

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.970

GnomAD3 exomes AF: 0.993 AC: 247487 AN: 249218 Hom.: 122946 AF XY: 0.995 AC XY: 134512 AN XY: 135202

Gnomad AFR exome AF: 0.908

Gnomad AMR exome AF: 0.995

Gnomad ASJ exome AF: 0.997

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.994

GnomAD4 exome AF: 0.997 AC: 1457301 AN: 1461666 Hom.: 726637 Cov.: 45 AF XY: 0.997 AC XY: 725234 AN XY: 727112

Gnomad4 AFR exome AF: 0.906

Gnomad4 AMR exome AF: 0.994

Gnomad4 ASJ exome AF: 0.996

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.993

GnomAD4 genome AF: 0.973 AC: 148217 AN: 152274 Hom.: 72243 Cov.: 32 AF XY: 0.974 AC XY: 72526 AN XY: 74448

Gnomad4 AFR AF: 0.911

Gnomad4 AMR AF: 0.986

Gnomad4 ASJ AF: 0.995

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.970

Alfa AF: 0.995 Hom.: 130642

Bravo AF: 0.970

TwinsUK AF: 1.00 AC: 3707

ALSPAC AF: 0.999 AC: 3852

ESP6500AA AF: 0.914 AC: 3541

ESP6500EA AF: 0.999 AC: 8270

ExAC AF: 0.992 AC: 119849

Asia WGS AF: 0.997 AC: 3466 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2014	- -

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.083
Dann	Benign	0.55
DEOGEN2	Benign	0.067	T;T;.
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.013	N
MetaRNN	Benign	6.6e-7	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.21	T
Polyphen		0.0010	B;B;.
Vest4		0.056
MPC		0.048
ClinPred		0.015	T
GERP RS		-9.7
Varity_R		0.020
gMVP		0.31

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: rs2438378; hg19: chr5-90119324;