rs137853919

Positions:

• chr5-90681308-C-T

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.5525-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 1,609,152 control chromosomes in the GnomAD database, including 53 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (51 hom.)
• Consequence: ADGRV1 ENST00000405460.9 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002221
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 0.311

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=-0.78).
• BP6: Variant 5-90681308-C-T is Benign according to our data. Variant chr5-90681308-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90681308-C-T is described in Lovd as [Likely_benign]. Variant chr5-90681308-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00437 (663/151764) while in subpopulation SAS AF= 0.00955 (46/4816). AF 95% confidence interval is 0.00736. There are 2 homozygotes in gnomad4. There are 326 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.5525-7C>T		splice_region_variant, 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.5525-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_032119.4	ENSP00000384582	P1

Frequencies

GnomAD3 genomes AF: 0.00437 AC: 663 AN: 151646 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000873

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00335

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00954

Gnomad FIN AF: 0.00517

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00687

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00516 AC: 1267 AN: 245678 Hom.: 10 AF XY: 0.00562 AC XY: 748 AN XY: 133118

Gnomad AFR exome AF: 0.000906

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00970

Gnomad FIN exome AF: 0.00531

Gnomad NFE exome AF: 0.00675

Gnomad OTH exome AF: 0.00758

GnomAD4 exome AF: 0.00626 AC: 9123 AN: 1457388 Hom.: 51 Cov.: 31 AF XY: 0.00654 AC XY: 4735 AN XY: 724516

Gnomad4 AFR exome AF: 0.000721

Gnomad4 AMR exome AF: 0.00175

Gnomad4 ASJ exome AF: 0.000308

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0103

Gnomad4 FIN exome AF: 0.00587

Gnomad4 NFE exome AF: 0.00662

Gnomad4 OTH exome AF: 0.00671

GnomAD4 genome AF: 0.00437 AC: 663 AN: 151764 Hom.: 2 Cov.: 32 AF XY: 0.00440 AC XY: 326 AN XY: 74118

Gnomad4 AFR AF: 0.000870

Gnomad4 AMR AF: 0.00335

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00955

Gnomad4 FIN AF: 0.00517

Gnomad4 NFE AF: 0.00687

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00568 Hom.: 0

Bravo AF: 0.00408

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00639

EpiControl AF: 0.00789

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6 Other:1

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ADGRV1: BP4, BS1, BS2 -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	5525-7C>T in intron 26 of GPR98: This variant is not expected to have clinical s ignificance because it has been identified in 0.8% (53/6588) of European America n chromosomes from a broad population by the NHLBI Exome sequencing project (htt p://evs.gs.washington.edu/EVS/; rs141528121). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 16, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 01, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2015	- -

Usher syndrome type 2C Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

ADGRV1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 13, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.8
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.024
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: rs137853919; hg19: chr5-89977125;