5-90647754-G-T

Position:

• chr5-90647754-G-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.3279G>T​(p.Leu1093Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 1,609,430 control chromosomes in the GnomAD database, including 366,496 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1093L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.74 (42871 hom., cov: 32)
  • Exomes 𝑓: 0.66 (323625 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.293

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 (MetaRNN=8.170927E-7).
• BP6: Variant 5-90647754-G-T is Benign according to our data. Variant chr5-90647754-G-T is described in ClinVar as [Benign]. Clinvar id is 46313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90647754-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.903 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.3279G>T	p.Leu1093Phe	missense_variant	17/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.3279G>T	p.Leu1093Phe	missense_variant	17/90	1	NM_032119.4	P1
ADGRV1	ENST00000640403.1	c.582G>T	p.Leu194Phe	missense_variant	7/29	5
ADGRV1	ENST00000504142.2	n.2045G>T		non_coding_transcript_exon_variant	11/14	5
ADGRV1	ENST00000639676.1	n.877G>T		non_coding_transcript_exon_variant	5/11	5

Frequencies

GnomAD3 genomes AF: 0.741 AC: 112562 AN: 151944 Hom.: 42800 Cov.: 32

Gnomad AFR AF: 0.910

Gnomad AMI AF: 0.716

Gnomad AMR AF: 0.780

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.812

Gnomad SAS AF: 0.727

Gnomad FIN AF: 0.662

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.640

Gnomad OTH AF: 0.748

GnomAD3 exomes AF: 0.711 AC: 176353 AN: 247886 Hom.: 63622 AF XY: 0.702 AC XY: 94449 AN XY: 134504

Gnomad AFR exome AF: 0.915

Gnomad AMR exome AF: 0.827

Gnomad ASJ exome AF: 0.669

Gnomad EAS exome AF: 0.801

Gnomad SAS exome AF: 0.719

Gnomad FIN exome AF: 0.670

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.704

GnomAD4 exome AF: 0.663 AC: 966248 AN: 1457368 Hom.: 323625 Cov.: 37 AF XY: 0.663 AC XY: 480374 AN XY: 724988

Gnomad4 AFR exome AF: 0.916

Gnomad4 AMR exome AF: 0.823

Gnomad4 ASJ exome AF: 0.670

Gnomad4 EAS exome AF: 0.817

Gnomad4 SAS exome AF: 0.719

Gnomad4 FIN exome AF: 0.668

Gnomad4 NFE exome AF: 0.637

Gnomad4 OTH exome AF: 0.690

GnomAD4 genome AF: 0.741 AC: 112688 AN: 152062 Hom.: 42871 Cov.: 32 AF XY: 0.744 AC XY: 55255 AN XY: 74314

Gnomad4 AFR AF: 0.911

Gnomad4 AMR AF: 0.780

Gnomad4 ASJ AF: 0.671

Gnomad4 EAS AF: 0.813

Gnomad4 SAS AF: 0.725

Gnomad4 FIN AF: 0.662

Gnomad4 NFE AF: 0.640

Gnomad4 OTH AF: 0.752

Alfa AF: 0.666 Hom.: 80850

Bravo AF: 0.761

TwinsUK AF: 0.629 AC: 2332

ALSPAC AF: 0.649 AC: 2502

ESP6500AA AF: 0.912 AC: 3338

ESP6500EA AF: 0.645 AC: 5258

ExAC AF: 0.709 AC: 85636

Asia WGS AF: 0.808 AC: 2809 AN: 3478

EpiCase AF: 0.652

EpiControl AF: 0.651

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 21, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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 = 4255/6556 (ESP data) -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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
AlphaMissense	Benign	0.035
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.29
DEOGEN2	Benign	0.047	T;T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.17	.;T;T
MetaRNN	Benign	8.2e-7	T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	0.99	P
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	2.8	.;N;.
REVEL	Benign	0.061
Sift	Benign	1.0	.;T;.
Sift4G	Benign	1.0	.;T;.
Polyphen		0.0	B;B;.
Vest4		0.028
MutPred		0.52		Gain of catalytic residue at L1093 (P = 0.2302);Gain of catalytic residue at L1093 (P = 0.2302);.;
MPC		0.050
ClinPred		0.00040	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2366777; hg19: chr5-89943571;