rs56329646

chr5-90716495-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_032119.4(ADGRV1):c.9213C>T(p.Asp3071=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00299 in 1,592,634 control chromosomes in the GnomAD database, including 18 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 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (16 hom.)
• Consequence: ADGRV1 NM_032119.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 0.860

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]

LOC105379077 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 5-90716495-C-T is Benign according to our data. Variant chr5-90716495-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46402.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=5, Likely_benign=1}. Variant chr5-90716495-C-T is described in Lovd as [Benign]. Variant chr5-90716495-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.86 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00305 (4392/1440442) while in subpopulation MID AF= 0.0178 (101/5676). AF 95% confidence interval is 0.015. There are 16 homozygotes in gnomad4_exome. There are 2219 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.9213C>T	p.Asp3071=	synonymous_variant	43/90	ENST00000405460.9
LOC105379077	XR_001742802.2	n.364-686G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.9213C>T	p.Asp3071=	synonymous_variant	43/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 366 AN: 152074 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00360

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00255 AC: 620 AN: 242924 Hom.: 5 AF XY: 0.00290 AC XY: 381 AN XY: 131576

Gnomad AFR exome AF: 0.000716

Gnomad AMR exome AF: 0.00172

Gnomad ASJ exome AF: 0.00206

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00268

Gnomad FIN exome AF: 0.000281

Gnomad NFE exome AF: 0.00384

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00305 AC: 4392 AN: 1440442 Hom.: 16 Cov.: 30 AF XY: 0.00311 AC XY: 2219 AN XY: 714574

Gnomad4 AFR exome AF: 0.00103

Gnomad4 AMR exome AF: 0.00198

Gnomad4 ASJ exome AF: 0.00169

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00304

Gnomad4 FIN exome AF: 0.000284

Gnomad4 NFE exome AF: 0.00331

Gnomad4 OTH exome AF: 0.00372

GnomAD4 genome AF: 0.00243 AC: 370 AN: 152192 Hom.: 2 Cov.: 33 AF XY: 0.00235 AC XY: 175 AN XY: 74412

Gnomad4 AFR AF: 0.000771

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00395

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00360

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00294 Hom.: 0

Bravo AF: 0.00248

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	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	Nov 01, 2023	ADGRV1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 01, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 20, 2012	Asp3071Asp in exon 43 of GPR98: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, has been identified in 0.4% (26/6554) of Europe an American chromosomes and 0.01% (3/2960) of African American chromosomes in a broad population by the NHLBI Exome sequencing project (http://evs.gs.washington .edu/EVS/; dbSNP rs56329646). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 06, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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	-0.31
Cadd	Benign	8.3
Dann	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs56329646; hg19: chr5-90012312; COSMIC: COSV67983312; COSMIC: COSV67983312;