rs17544552

chr5-90683701-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.5780C>T(p.Thr1927Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0749 in 1,613,630 control chromosomes in the GnomAD database, including 5,014 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. T1927T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.069 (418 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4596 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -1.32

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=0.0014486611).
• BP6: Variant 5-90683701-C-T is Benign according to our data. Variant chr5-90683701-C-T is described in ClinVar as [Benign]. Clinvar id is 46339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90683701-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.5780C>T	p.Thr1927Met	missense_variant	28/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.5780C>T	p.Thr1927Met	missense_variant	28/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.0693 AC: 10530 AN: 152030 Hom.: 419 Cov.: 32

Gnomad AFR AF: 0.0592

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0608

Gnomad ASJ AF: 0.0807

Gnomad EAS AF: 0.0179

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0487

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0798

Gnomad OTH AF: 0.0708

GnomAD3 exomes AF: 0.0717 AC: 17827 AN: 248806 Hom.: 770 AF XY: 0.0760 AC XY: 10253 AN XY: 134950

Gnomad AFR exome AF: 0.0624

Gnomad AMR exome AF: 0.0441

Gnomad ASJ exome AF: 0.0823

Gnomad EAS exome AF: 0.0178

Gnomad SAS exome AF: 0.121

Gnomad FIN exome AF: 0.0460

Gnomad NFE exome AF: 0.0804

Gnomad OTH exome AF: 0.0753

GnomAD4 exome AF: 0.0755 AC: 110293 AN: 1461482 Hom.: 4596 Cov.: 33 AF XY: 0.0773 AC XY: 56226 AN XY: 726992

Gnomad4 AFR exome AF: 0.0571

Gnomad4 AMR exome AF: 0.0464

Gnomad4 ASJ exome AF: 0.0822

Gnomad4 EAS exome AF: 0.00993

Gnomad4 SAS exome AF: 0.120

Gnomad4 FIN exome AF: 0.0513

Gnomad4 NFE exome AF: 0.0768

Gnomad4 OTH exome AF: 0.0781

GnomAD4 genome AF: 0.0692 AC: 10533 AN: 152148 Hom.: 418 Cov.: 32 AF XY: 0.0687 AC XY: 5110 AN XY: 74378

Gnomad4 AFR AF: 0.0594

Gnomad4 AMR AF: 0.0607

Gnomad4 ASJ AF: 0.0807

Gnomad4 EAS AF: 0.0178

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.0487

Gnomad4 NFE AF: 0.0798

Gnomad4 OTH AF: 0.0696

Alfa AF: 0.0790 Hom.: 1095

Bravo AF: 0.0663

TwinsUK AF: 0.0852 AC: 316

ALSPAC AF: 0.0786 AC: 303

ESP6500AA AF: 0.0600 AC: 234

ESP6500EA AF: 0.0792 AC: 655

ExAC AF: 0.0738 AC: 8916

Asia WGS AF: 0.0620 AC: 214 AN: 3478

EpiCase AF: 0.0862

EpiControl AF: 0.0873

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 30, 2010	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	1.5
Dann	Benign	0.89
DEOGEN2	Benign	0.10	T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.076	N
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.23	T
Polyphen		0.098	B;B;.
Vest4		0.021
MPC		0.081
ClinPred		0.016	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.47

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: rs17544552; hg19: chr5-89979518; COSMIC: COSV67985300;