rs186639101

Positions:

• chr5-90627624-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_032119.4(ADGRV1):​c.1086A>G​(p.Leu362=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,613,936 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (15 hom.)
• Consequence: ADGRV1 NM_032119.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -0.207

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 5-90627624-A-G is Benign according to our data. Variant chr5-90627624-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158643.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=4}. Variant chr5-90627624-A-G is described in Lovd as [Likely_benign]. Variant chr5-90627624-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.207 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00223 (3255/1461652) while in subpopulation SAS AF= 0.00787 (679/86254). AF 95% confidence interval is 0.00738. There are 15 homozygotes in gnomad4_exome. There are 1814 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.1086A>G	p.Leu362=	synonymous_variant	7/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.1086A>G	p.Leu362=	synonymous_variant	7/90	1	NM_032119.4	P1
ADGRV1	ENST00000640281.1	n.1145A>G		non_coding_transcript_exon_variant	7/7	1
ADGRV1	ENST00000640083.1	n.791A>G		non_coding_transcript_exon_variant	5/6	5
ADGRV1	ENST00000640109.1	n.1182A>G		non_coding_transcript_exon_variant	7/9	5

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00238 AC: 593 AN: 249118 Hom.: 3 AF XY: 0.00300 AC XY: 406 AN XY: 135144

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000811

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00765

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00239

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00223 AC: 3255 AN: 1461652 Hom.: 15 Cov.: 32 AF XY: 0.00249 AC XY: 1814 AN XY: 727108

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00375

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00787

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00203

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74454

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00188

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00190 Hom.: 0

Bravo AF: 0.00162

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00327

EpiControl AF: 0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ADGRV1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2019	- -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 10, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 20, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 18, 2016	Leu362Leu in Exon 07 of GPR98: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.8% (125/16500) of S outh Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs186639101). -

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, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 20, 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
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.7
DANN	Benign	0.67

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: rs186639101; hg19: chr5-89923441;