rs202190568

chr5-90763396-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_032119.4(ADGRV1):c.12212G>A(p.Arg4071Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000839 in 1,613,418 control chromosomes in the GnomAD database, including 1 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 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (1 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: -0.411

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018234879).
• BP6: Variant 5-90763396-G-A is Benign according to our data. Variant chr5-90763396-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178366.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}. Variant chr5-90763396-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.12212G>A	p.Arg4071Gln	missense_variant	59/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.12212G>A	p.Arg4071Gln	missense_variant	59/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.000704 AC: 107 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00124

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000719 AC: 179 AN: 249010 Hom.: 1 AF XY: 0.000792 AC XY: 107 AN XY: 135094

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000853 AC: 1247 AN: 1461328 Hom.: 1 Cov.: 32 AF XY: 0.000854 AC XY: 621 AN XY: 726952

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00103

Gnomad4 OTH exome AF: 0.000862

GnomAD4 genome AF: 0.000704 AC: 107 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.000767 AC XY: 57 AN XY: 74292

Gnomad4 AFR AF: 0.000386

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00124

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00120 Hom.: 2

Bravo AF: 0.000672

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000852 AC: 7

ExAC AF: 0.000646 AC: 78

EpiCase AF: 0.00109

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 06, 2016	p.Arg4071Gln in exon 59 of GPR98: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, more than 10 different mammals have a glutamine (Gln) at this position despite high nearby amino acid conservation. In addition, this variant was iden tified in 0.1% (74/66372) of European chromosomes by the Exome Aggregation Conso rtium (ExAC, http://exac.broadinstitute.org; dbSNP rs202190568). -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 09, 2022	Variant summary: ADGRV1 c.12212G>A (p.Arg4071Gln) results in a conservative amino acid change located in the Na-Ca exchanger/integrin-beta4 domain (IPR003644) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 249010 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in ADGRV1 causing Usher Syndrome (0.00072 vs 0.0054), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.12212G>A in individuals affected with features of ADGRV1-Related Disorders such as Usher Syndrome type 2C or Familial Febrile Seizures 4 and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3; Likely Benign, n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Usher syndrome type 2C Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	0.069
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	4.5
Dann	Benign	0.61
DEOGEN2	Benign	0.047	T;T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.024	N
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
Polyphen		0.032	B;B;.
Vest4		0.11
MVP		0.14
MPC		0.062
ClinPred		0.0079	T
GERP RS		-0.32
Varity_R		0.038
gMVP		0.32

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: rs202190568; hg19: chr5-90059213; COSMIC: COSV67982892; COSMIC: COSV67982892;