rs113938044

chr5-90728767-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_032119.4(ADGRV1):c.10260C>T(p.Phe3420=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,613,966 control chromosomes in the GnomAD database, including 8 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 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (7 hom.)
• Consequence: ADGRV1 NM_032119.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 0.762

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 5-90728767-C-T is Benign according to our data. Variant chr5-90728767-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46246.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=3}. Variant chr5-90728767-C-T is described in Lovd as [Benign]. Variant chr5-90728767-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.762 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.10260C>T	p.Phe3420=	synonymous_variant	49/90	ENST00000405460.9
LOC105379077	XR_001742802.2	n.363+12140G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.10260C>T	p.Phe3420=	synonymous_variant	49/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 217 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00148 AC: 370 AN: 249202 Hom.: 0 AF XY: 0.00145 AC XY: 196 AN XY: 135192

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.00190 AC: 2771 AN: 1461660 Hom.: 7 Cov.: 31 AF XY: 0.00183 AC XY: 1334 AN XY: 727104

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.00256

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00108

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.00206

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.00142 AC: 217 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74478

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00201

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00194 Hom.: 0

Bravo AF: 0.00165

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ADGRV1: BP4, BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2019	This variant is associated with the following publications: (PMID: 22135276) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Invitae	Jan 31, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 02, 2017	p.Phe3420Phe in exon 49 of GPR98: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, has been identified in 0.3% (27/10150) of Ash kenazi Jewish chromosomes, 0.2% (229/126674) European chromosomes, and 0.2% (57/ 34414) Latino chromosomes by the Genome Aggregation Database (http://gnomad.broa dinstitute.org; dbSNP rs113938044) and is reported as benign in one publication (Le Quesne 2012). -
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 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, 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	-0.40
Cadd	Benign	7.1
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113938044; hg19: chr5-90024584;