rs61740119

Positions:

• chr5-90653834-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_032119.4(ADGRV1):​c.4260A>G​(p.Glu1420Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,612,894 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (46 hom.)
• Consequence: ADGRV1 NM_032119.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.780

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]

ADGRV1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 5-90653834-A-G is Benign according to our data. Variant chr5-90653834-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 46327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90653834-A-G is described in Lovd as [Likely_benign]. Variant chr5-90653834-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.78 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00549 (836/152328) while in subpopulation SAS AF= 0.0126 (61/4830). AF 95% confidence interval is 0.0101. There are 3 homozygotes in gnomad4. There are 408 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.4260A>G	p.Glu1420Glu	synonymous_variant	20/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.4260A>G	p.Glu1420Glu	synonymous_variant	20/90	1	NM_032119.4	ENSP00000384582.2
ADGRV1	ENST00000640403.1	c.1551A>G	p.Glu517Glu	synonymous_variant	10/29	5		ENSP00000492531.1
ADGRV1	ENST00000504142.2	n.3026A>G		non_coding_transcript_exon_variant	14/14	5
ADGRV1	ENST00000639676.1	n.1858A>G		non_coding_transcript_exon_variant	8/11	5

Frequencies

GnomAD3 genomes AF: 0.00552 AC: 840 AN: 152210 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00982

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00332

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00562 AC: 1387 AN: 246698 Hom.: 8 AF XY: 0.00594 AC XY: 794 AN XY: 133754

Gnomad AFR exome AF: 0.00992

Gnomad AMR exome AF: 0.00728

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0136

Gnomad FIN exome AF: 0.00205

Gnomad NFE exome AF: 0.00306

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.00407 AC: 5943 AN: 1460566 Hom.: 46 Cov.: 32 AF XY: 0.00432 AC XY: 3138 AN XY: 726394

Gnomad4 AFR exome AF: 0.00938

Gnomad4 AMR exome AF: 0.00694

Gnomad4 ASJ exome AF: 0.0118

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0133

Gnomad4 FIN exome AF: 0.00253

Gnomad4 NFE exome AF: 0.00288

Gnomad4 OTH exome AF: 0.00588

GnomAD4 genome AF: 0.00549 AC: 836 AN: 152328 Hom.: 3 Cov.: 32 AF XY: 0.00548 AC XY: 408 AN XY: 74482

Gnomad4 AFR AF: 0.00977

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0126

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00332

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00472 Hom.: 1

Bravo AF: 0.00564

Asia WGS AF: 0.00491 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ADGRV1: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2023	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 28, 2012	Glu1420Glu in exon 20 of GPR98: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence and has been identified in 0.4% (33/8180) of Eu ropean American chromosomes and 1.1% (42/3706) of African American chromosomes f rom a broad population by the NHLBI Exome sequencing project (http://evs.gs.wash ington.edu/EVS/; dbSNP rs61740119). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2013	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	Genetic Services Laboratory, University of Chicago	Apr 21, 2014	- -

Usher syndrome type 2C Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.4
DANN	Benign	0.56

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: rs61740119; hg19: chr5-89949651;