rs10040165

Positions:

• chr5-90692595-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_032119.4(ADGRV1):​c.6952-10G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 1,584,942 control chromosomes in the GnomAD database, including 94,667 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8057 hom., cov: 32)
  • Exomes 𝑓: 0.34 (86610 hom.)
• Consequence: ADGRV1 NM_032119.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001884
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.469

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 5-90692595-G-A is Benign according to our data. Variant chr5-90692595-G-A is described in ClinVar as [Benign]. Clinvar id is 46358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90692595-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.6952-10G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.6952-10G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_032119.4	ENSP00000384582	P1

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47886 AN: 151806 Hom.: 8044 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.348

GnomAD3 exomes AF: 0.348 AC: 78709 AN: 226266 Hom.: 14771 AF XY: 0.341 AC XY: 41921 AN XY: 122810

Gnomad AFR exome AF: 0.204

Gnomad AMR exome AF: 0.565

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.361

Gnomad SAS exome AF: 0.309

Gnomad FIN exome AF: 0.332

Gnomad NFE exome AF: 0.327

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.342 AC: 490657 AN: 1433018 Hom.: 86610 Cov.: 29 AF XY: 0.340 AC XY: 242185 AN XY: 711990

Gnomad4 AFR exome AF: 0.202

Gnomad4 AMR exome AF: 0.553

Gnomad4 ASJ exome AF: 0.269

Gnomad4 EAS exome AF: 0.432

Gnomad4 SAS exome AF: 0.322

Gnomad4 FIN exome AF: 0.340

Gnomad4 NFE exome AF: 0.340

Gnomad4 OTH exome AF: 0.334

GnomAD4 genome AF: 0.315 AC: 47905 AN: 151924 Hom.: 8057 Cov.: 32 AF XY: 0.319 AC XY: 23647 AN XY: 74230

Gnomad4 AFR AF: 0.215

Gnomad4 AMR AF: 0.472

Gnomad4 ASJ AF: 0.276

Gnomad4 EAS AF: 0.387

Gnomad4 SAS AF: 0.322

Gnomad4 FIN AF: 0.334

Gnomad4 NFE AF: 0.333

Gnomad4 OTH AF: 0.344

Alfa AF: 0.335 Hom.: 10181

Bravo AF: 0.327

Asia WGS AF: 0.343 AC: 1193 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2009	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -

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	- -

Usher syndrome type 2C Benign:1

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. -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.018
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: rs10040165; hg19: chr5-89988412; COSMIC: COSV67980893; COSMIC: COSV67980893;