rs190922596

chr5-90647666-A-Cchr5-90647666-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.3191A>C(p.Glu1064Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,613,958 control chromosomes in the GnomAD database, including 7 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 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (7 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: 0.937

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=0.007806927).
• BP6: Variant 5-90647666-A-C is Benign according to our data. Variant chr5-90647666-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46312.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=7}. Variant chr5-90647666-A-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.3191A>C	p.Glu1064Ala	missense_variant	17/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.3191A>C	p.Glu1064Ala	missense_variant	17/90	1	NM_032119.4	P1
ADGRV1	ENST00000640403.1	c.494A>C	p.Glu165Ala	missense_variant	7/29	5
ADGRV1	ENST00000504142.2	n.1957A>C		non_coding_transcript_exon_variant	11/14	5
ADGRV1	ENST00000639676.1	n.789A>C		non_coding_transcript_exon_variant	5/11	5

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00268

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00206 AC: 513 AN: 249068 Hom.: 2 AF XY: 0.00197 AC XY: 266 AN XY: 135106

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00310

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00246

Gnomad NFE exome AF: 0.00298

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00212 AC: 3096 AN: 1461660 Hom.: 7 Cov.: 33 AF XY: 0.00201 AC XY: 1463 AN XY: 727110

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00247

Gnomad4 NFE exome AF: 0.00244

Gnomad4 OTH exome AF: 0.00195

GnomAD4 genome AF: 0.00189 AC: 288 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.00187 AC XY: 139 AN XY: 74476

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00202 Hom.: 1

Bravo AF: 0.00171

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000528 AC: 2

ESP6500EA AF: 0.00268 AC: 22

ExAC AF: 0.00218 AC: 264

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ADGRV1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2020	This variant is associated with the following publications: (PMID: 23804846, 22334370) -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 02, 2019	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 21, 2017	p.Glu1064Ala in exon 17 of ADGRV1: This variant is not expected to have clinical significance because it has been identified in 0.3% (371/126508) of European ch romosomes including one homozygote by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org; dbSNP rs190922596). ACMG?AMP criteria applied: BS1 -

Febrile seizures, familial, 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 27, 2013

- -

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. -

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

DBGen Ocular Genomics

Jan 01, 2021

Class 3 ACMG Guidelines, 2015 -

ADGRV1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2019

This variant is classified as likely 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	0.092
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	13
Dann	Benign	0.95
DEOGEN2	Benign	0.072	T;T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.42	N
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0078	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.82	N
PrimateAI	Benign	0.28	T
Polyphen		0.0010	B;B;.
Vest4		0.051
MVP		0.37
MPC		0.050
ClinPred		0.0045	T
GERP RS		3.3
Varity_R		0.11
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: rs190922596; hg19: chr5-89943483; COSMIC: COSV67982057;