rs201586455

Positions:

• chr5-90706355-A-C
• chr5-90706355-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_032119.4(ADGRV1):​c.8691A>C​(p.Glu2897Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 1,612,490 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (38 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 2.02

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068282783).
• BP6: Variant 5-90706355-A-C is Benign according to our data. Variant chr5-90706355-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46396.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Likely_benign=2, Uncertain_significance=1}. Variant chr5-90706355-A-C is described in Lovd as [Benign]. Variant chr5-90706355-A-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 4 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.8691A>C	p.Glu2897Asp	missense_variant	38/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.8691A>C	p.Glu2897Asp	missense_variant	38/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.00383 AC: 582 AN: 152036 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00566

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00419 AC: 1034 AN: 246904 Hom.: 5 AF XY: 0.00432 AC XY: 578 AN XY: 133912

Gnomad AFR exome AF: 0.00156

Gnomad AMR exome AF: 0.00251

Gnomad ASJ exome AF: 0.0209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000562

Gnomad FIN exome AF: 0.00181

Gnomad NFE exome AF: 0.00569

Gnomad OTH exome AF: 0.00383

GnomAD4 exome AF: 0.00557 AC: 8141 AN: 1460336 Hom.: 38 Cov.: 32 AF XY: 0.00549 AC XY: 3987 AN XY: 726296

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00249

Gnomad4 ASJ exome AF: 0.0202

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000757

Gnomad4 FIN exome AF: 0.00247

Gnomad4 NFE exome AF: 0.00617

Gnomad4 OTH exome AF: 0.00663

GnomAD4 genome AF: 0.00383 AC: 582 AN: 152154 Hom.: 4 Cov.: 32 AF XY: 0.00349 AC XY: 260 AN XY: 74400

Gnomad4 AFR AF: 0.000987

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00161

Gnomad4 NFE AF: 0.00566

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00599 Hom.: 11

Bravo AF: 0.00386

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00189 AC: 7

ESP6500EA AF: 0.00706 AC: 58

ExAC AF: 0.00411 AC: 496

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Glu2897Asp in Exon 38 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (45/6620) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 18, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	ADGRV1: BP4, BS2 -
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	Invitae	Jan 31, 2024	- -

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. -

ADGRV1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.064	T;T;.
Eigen	Benign	-0.078
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.0068	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.94	D
PrimateAI	Benign	0.42	T
Polyphen		0.54	P;P;.
Vest4		0.37
MutPred		0.54		Loss of catalytic residue at E2897 (P = 0.261);Loss of catalytic residue at E2897 (P = 0.261);.;
MVP		0.40
MPC		0.31
ClinPred		0.016	T
GERP RS		4.0
Varity_R		0.13
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs201586455; hg19: chr5-90002172;