rs73181640

Positions:

• chr5-90643052-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000405460.9(ADGRV1):​c.2553+11T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,602,940 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (59 hom.)
• Consequence: ADGRV1 ENST00000405460.9 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.671

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 5-90643052-T-A is Benign according to our data. Variant chr5-90643052-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 46307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90643052-T-A is described in Lovd as [Benign]. Variant chr5-90643052-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00605 (922/152292) while in subpopulation SAS AF= 0.0187 (90/4824). AF 95% confidence interval is 0.0155. There are 4 homozygotes in gnomad4. There are 472 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.2553+11T>A		intron_variant		ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.2553+11T>A		intron_variant		1	NM_032119.4	ENSP00000384582	P1
ADGRV1	ENST00000640403.1	c.-145+11T>A		intron_variant		5		ENSP00000492531
ADGRV1	ENST00000504142.2	n.1319+11T>A		intron_variant, non_coding_transcript_variant		5
ADGRV1	ENST00000639676.1	n.151+11T>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00606 AC: 922 AN: 152174 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00592 AC: 1465 AN: 247328 Hom.: 17 AF XY: 0.00675 AC XY: 906 AN XY: 134268

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.00324

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.0221

Gnomad FIN exome AF: 0.00154

Gnomad NFE exome AF: 0.00220

Gnomad OTH exome AF: 0.00687

GnomAD4 exome AF: 0.00339 AC: 4921 AN: 1450648 Hom.: 59 Cov.: 28 AF XY: 0.00392 AC XY: 2835 AN XY: 722354

Gnomad4 AFR exome AF: 0.0133

Gnomad4 AMR exome AF: 0.00299

Gnomad4 ASJ exome AF: 0.0136

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0202

Gnomad4 FIN exome AF: 0.00176

Gnomad4 NFE exome AF: 0.00151

Gnomad4 OTH exome AF: 0.00525

GnomAD4 genome AF: 0.00605 AC: 922 AN: 152292 Hom.: 4 Cov.: 32 AF XY: 0.00634 AC XY: 472 AN XY: 74470

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0187

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00181

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00626 Hom.: 2

Bravo AF: 0.00588

Asia WGS AF: 0.00953 AC: 34 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	2553+11T>A in Intron 13 of GPR98: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence and has been identified in 1.5% (43/2906) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.was hington.edu/EVS; dbSNP rs73181640). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 13, 2017	- -

not provided Benign:4

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	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 2C Benign:1

Likely benign, 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 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	-0.80
CADD	Benign	7.5
DANN	Benign	0.76

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: rs73181640; hg19: chr5-89938869;