5-90642770-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032119.4(ADGRV1):c.2367+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.696 in 1,607,338 control chromosomes in the GnomAD database, including 393,400 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (45027 hom., cov: 32)
  • Exomes 𝑓: 0.69 (348373 hom.)
• Consequence: ADGRV1 NM_032119.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001225
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.448

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=-0.88).
• BP6: Variant 5-90642770-C-T is Benign according to our data. Variant chr5-90642770-C-T is described in ClinVar as [Benign]. Clinvar id is 46305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90642770-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.2367+8C>T		splice_region_variant, intron_variant		ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.2367+8C>T		splice_region_variant, intron_variant		1	NM_032119.4	P1
ADGRV1	ENST00000640403.1	c.-331+8C>T		splice_region_variant, intron_variant		5
ADGRV1	ENST00000504142.2	n.1133+8C>T		splice_region_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.761 AC: 115669 AN: 151958 Hom.: 44952 Cov.: 32

Gnomad AFR AF: 0.920

Gnomad AMI AF: 0.736

Gnomad AMR AF: 0.789

Gnomad ASJ AF: 0.696

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.753

Gnomad FIN AF: 0.684

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.671

Gnomad OTH AF: 0.754

GnomAD3 exomes AF: 0.733 AC: 178748 AN: 243920 Hom.: 66205 AF XY: 0.725 AC XY: 95870 AN XY: 132310

Gnomad AFR exome AF: 0.925

Gnomad AMR exome AF: 0.835

Gnomad ASJ exome AF: 0.688

Gnomad EAS exome AF: 0.807

Gnomad SAS exome AF: 0.748

Gnomad FIN exome AF: 0.690

Gnomad NFE exome AF: 0.672

Gnomad OTH exome AF: 0.729

GnomAD4 exome AF: 0.689 AC: 1003013 AN: 1455262 Hom.: 348373 Cov.: 41 AF XY: 0.689 AC XY: 498711 AN XY: 723828

Gnomad4 AFR exome AF: 0.926

Gnomad4 AMR exome AF: 0.830

Gnomad4 ASJ exome AF: 0.693

Gnomad4 EAS exome AF: 0.821

Gnomad4 SAS exome AF: 0.747

Gnomad4 FIN exome AF: 0.689

Gnomad4 NFE exome AF: 0.666

Gnomad4 OTH exome AF: 0.714

GnomAD4 genome AF: 0.761 AC: 115801 AN: 152076 Hom.: 45027 Cov.: 32 AF XY: 0.763 AC XY: 56725 AN XY: 74316

Gnomad4 AFR AF: 0.920

Gnomad4 AMR AF: 0.789

Gnomad4 ASJ AF: 0.696

Gnomad4 EAS AF: 0.819

Gnomad4 SAS AF: 0.751

Gnomad4 FIN AF: 0.684

Gnomad4 NFE AF: 0.671

Gnomad4 OTH AF: 0.758

Alfa AF: 0.690 Hom.: 23822

Bravo AF: 0.778

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Feb 02, 2012	Caucasian frequency = 4403/6528 (LMM data) -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
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)	May 09, 2013	- -

Usher syndrome type 2C Benign:2

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	3.1
Dann	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
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: rs2366773; hg19: chr5-89938587;