rs7729495

chr5-90807670-T-Cchr5-90807670-T-G

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.14905T>C(p.Trp4969Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00886 in 1,612,550 control chromosomes in the GnomAD database, including 1,125 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (578 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (547 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.13

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=0.0015814304).
• BP6: Variant 5-90807670-T-C is Benign according to our data. Variant chr5-90807670-T-C is described in ClinVar as [Benign]. Clinvar id is 46274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.14905T>C	p.Trp4969Arg	missense_variant	73/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.14905T>C	p.Trp4969Arg	missense_variant	73/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.0464 AC: 7061 AN: 152194 Hom.: 576 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.0122 AC: 3041 AN: 249102 Hom.: 232 AF XY: 0.00937 AC XY: 1267 AN XY: 135164

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.00792

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000301

Gnomad OTH exome AF: 0.00479

GnomAD4 exome AF: 0.00493 AC: 7201 AN: 1460238 Hom.: 547 Cov.: 30 AF XY: 0.00432 AC XY: 3137 AN XY: 726308

Gnomad4 AFR exome AF: 0.172

Gnomad4 AMR exome AF: 0.00868

Gnomad4 ASJ exome AF: 0.00387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000558

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000186

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.0466 AC: 7093 AN: 152312 Hom.: 578 Cov.: 32 AF XY: 0.0447 AC XY: 3331 AN XY: 74472

Gnomad4 AFR AF: 0.163

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.00653 Hom.: 138

Bravo AF: 0.0537

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.168 AC: 619

ESP6500EA AF: 0.000611 AC: 5

ExAC AF: 0.0152 AC: 1833

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.000548

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 14, 2012	Trp4969Arg in Exon 73 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 16.6% (495/2990) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs7729495). -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 02, 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:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 30, 2017	- -

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	0.048
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	15
Dann	Benign	0.43
DEOGEN2	Benign	0.071	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.0060	N
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.20	T
Polyphen		0.0	B;B;.
Vest4		0.053
MutPred		0.41		Gain of disorder (P = 0.0084);Gain of disorder (P = 0.0084);.;
MPC		0.075
ClinPred		0.0036	T
GERP RS		4.8
Varity_R		0.073
gMVP		0.23

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: rs7729495; hg19: chr5-90103487;