rs17554631

Positions:

• chr5-90784003-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000405460.9(ADGRV1):​c.13599A>G​(p.Thr4533=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,610,940 control chromosomes in the GnomAD database, including 34,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2448 hom., cov: 32)
  • Exomes 𝑓: 0.20 (32520 hom.)
• Consequence: ADGRV1 ENST00000405460.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.430

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 5-90784003-A-G is Benign according to our data. Variant chr5-90784003-A-G is described in ClinVar as [Benign]. Clinvar id is 46268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90784003-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.13599A>G	p.Thr4533=	synonymous_variant	67/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.13599A>G	p.Thr4533=	synonymous_variant	67/90	1	NM_032119.4	ENSP00000384582	P1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23447 AN: 152000 Hom.: 2447 Cov.: 32

Gnomad AFR AF: 0.0404

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.166

GnomAD3 exomes AF: 0.162 AC: 40096 AN: 246750 Hom.: 4175 AF XY: 0.165 AC XY: 22116 AN XY: 133766

Gnomad AFR exome AF: 0.0362

Gnomad AMR exome AF: 0.0963

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.00291

Gnomad SAS exome AF: 0.101

Gnomad FIN exome AF: 0.274

Gnomad NFE exome AF: 0.222

Gnomad OTH exome AF: 0.185

GnomAD4 exome AF: 0.201 AC: 293874 AN: 1458822 Hom.: 32520 Cov.: 32 AF XY: 0.199 AC XY: 144460 AN XY: 725636

Gnomad4 AFR exome AF: 0.0342

Gnomad4 AMR exome AF: 0.102

Gnomad4 ASJ exome AF: 0.143

Gnomad4 EAS exome AF: 0.00184

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.270

Gnomad4 NFE exome AF: 0.225

Gnomad4 OTH exome AF: 0.180

GnomAD4 genome AF: 0.154 AC: 23449 AN: 152118 Hom.: 2448 Cov.: 32 AF XY: 0.154 AC XY: 11444 AN XY: 74356

Gnomad4 AFR AF: 0.0403

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.00308

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.279

Gnomad4 NFE AF: 0.223

Gnomad4 OTH AF: 0.169

Alfa AF: 0.200 Hom.: 4156

Bravo AF: 0.138

Asia WGS AF: 0.0640 AC: 221 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 23, 2010	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 26, 2016	- -

Usher syndrome type 2C Benign:2

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Febrile seizures, familial, 4;C2931213:Usher syndrome type 2C Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.4
DANN	Benign	0.72

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: rs17554631; hg19: chr5-90079820;