rs72782753

chr5-90674063-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_032119.4(ADGRV1):c.4939A>G(p.Ile1647Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00638 in 1,608,794 control chromosomes in the GnomAD database, including 53 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I1647I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (53 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.222

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047038198).
• BP6: Variant 5-90674063-A-G is Benign according to our data. Variant chr5-90674063-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46331.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=4, Uncertain_significance=1}. Variant chr5-90674063-A-G is described in Lovd as [Benign]. Variant chr5-90674063-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00496 (755/152260) while in subpopulation NFE AF= 0.00779 (530/68018). AF 95% confidence interval is 0.00724. There are 0 homozygotes in gnomad4. There are 346 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.4939A>G	p.Ile1647Val	missense_variant	23/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.4939A>G	p.Ile1647Val	missense_variant	23/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.00496 AC: 755 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00781

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00461 AC: 1139 AN: 247216 Hom.: 3 AF XY: 0.00461 AC XY: 618 AN XY: 134116

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00512

Gnomad ASJ exome AF: 0.000798

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00234

Gnomad FIN exome AF: 0.00274

Gnomad NFE exome AF: 0.00700

Gnomad OTH exome AF: 0.00418

GnomAD4 exome AF: 0.00653 AC: 9511 AN: 1456534 Hom.: 53 Cov.: 28 AF XY: 0.00647 AC XY: 4688 AN XY: 724802

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00526

Gnomad4 ASJ exome AF: 0.000614

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00231

Gnomad4 FIN exome AF: 0.00268

Gnomad4 NFE exome AF: 0.00770

Gnomad4 OTH exome AF: 0.00558

GnomAD4 genome AF: 0.00496 AC: 755 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.00465 AC XY: 346 AN XY: 74438

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00680

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00779

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00663 Hom.: 6

Bravo AF: 0.00507

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.000819 AC: 3

ESP6500EA AF: 0.00686 AC: 56

ExAC AF: 0.00428 AC: 517

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.00676

EpiControl AF: 0.00749

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 18, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Ile1647Val in Exon 23 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (43/6558) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs72782753). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 13, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ADGRV1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 08, 2018	- -

Usher syndrome type 2C Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	4.9
Dann	Benign	0.56
DEOGEN2	Benign	0.054	T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.67	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0047	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
Polyphen		0.0010	B;B;.
Vest4		0.12
MVP		0.16
MPC		0.044
ClinPred		0.0045	T
GERP RS		-10
Varity_R		0.027
gMVP		0.27

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: rs72782753; hg19: chr5-89969880;