rs187039736

chr5-90863868-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_032119.4(ADGRV1):c.17856+11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00319 in 1,552,176 control chromosomes in the GnomAD database, including 25 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 0.0026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (25 hom.)
• Consequence: ADGRV1 NM_032119.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -2.50

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 5-90863868-G-A is Benign according to our data. Variant chr5-90863868-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46294.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}. Variant chr5-90863868-G-A is described in Lovd as [Benign]. Variant chr5-90863868-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 4 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.17856+11G>A		intron_variant		ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.17856+11G>A		intron_variant		1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.00257 AC: 391 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00369

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00275 AC: 678 AN: 246768 Hom.: 4 AF XY: 0.00265 AC XY: 354 AN XY: 133786

Gnomad AFR exome AF: 0.000583

Gnomad AMR exome AF: 0.000792

Gnomad ASJ exome AF: 0.0209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000599

Gnomad FIN exome AF: 0.000420

Gnomad NFE exome AF: 0.00343

Gnomad OTH exome AF: 0.00403

GnomAD4 exome AF: 0.00326 AC: 4560 AN: 1399946 Hom.: 25 Cov.: 22 AF XY: 0.00311 AC XY: 2178 AN XY: 699808

Gnomad4 AFR exome AF: 0.000870

Gnomad4 AMR exome AF: 0.00102

Gnomad4 ASJ exome AF: 0.0212

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000864

Gnomad4 FIN exome AF: 0.000413

Gnomad4 NFE exome AF: 0.00345

Gnomad4 OTH exome AF: 0.00348

GnomAD4 genome AF: 0.00257 AC: 391 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74426

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00369

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00398 Hom.: 1

Bravo AF: 0.00256

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:2

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	Apr 30, 2012	17856+11G>A in Intron 83 of GPR98: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence and has been identified in 0.4% (27/6622) of European American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS). -

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
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.0080
Dann	Benign	0.65

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: rs187039736; hg19: chr5-90159685;