rs13157270

Variant names:

• chr5-90716562-G-A
• rs13157270
• NM_032119.4:c.9280G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032119.4(ADGRV1):​c.9280G>A​(p.Val3094Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0777 in 1,613,136 control chromosomes in the GnomAD database, including 5,355 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3094A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.064 (415 hom., cov: 32)
  • Exomes 𝑓: 0.079 (4940 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.23
• Publications: 22 publications found

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]

ADGRV1 Gene-Disease associations (from GenCC):

• Usher syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2C

  Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• febrile seizures, familial, 4

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

LOC105379077 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020315647).
• BP6: Variant 5-90716562-G-A is Benign according to our data. Variant chr5-90716562-G-A is described in ClinVar as Benign. ClinVar VariationId is 46403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0865 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.9280G>A	p.Val3094Ile	missense_variant	Exon 43 of 90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.9280G>A	p.Val3094Ile	missense_variant	Exon 43 of 90	1	NM_032119.4	ENSP00000384582.2

Frequencies

GnomAD3 genomes AF: 0.0639 AC: 9713 AN: 152058 Hom.: 415 Cov.: 32

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.0413

Gnomad ASJ AF: 0.0648

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.0643

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0884

Gnomad OTH AF: 0.0603

GnomAD2 exomes AF: 0.0677 AC: 16817 AN: 248542 AF XY: 0.0700

Gnomad AFR exome AF: 0.0248

Gnomad AMR exome AF: 0.0323

Gnomad ASJ exome AF: 0.0674

Gnomad EAS exome AF: 0.00285

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.0873

Gnomad OTH exome AF: 0.0742

GnomAD4 exome AF: 0.0791 AC: 115635 AN: 1460960 Hom.: 4940 Cov.: 31 AF XY: 0.0790 AC XY: 57426 AN XY: 726782

African (AFR) AF: 0.0238 AC: 796 AN: 33478

American (AMR) AF: 0.0343 AC: 1532 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0666 AC: 1740 AN: 26124

East Asian (EAS) AF: 0.00154 AC: 61 AN: 39670

South Asian (SAS) AF: 0.0633 AC: 5457 AN: 86212

European-Finnish (FIN) AF: 0.107 AC: 5692 AN: 53376

Middle Eastern (MID) AF: 0.0846 AC: 488 AN: 5766

European-Non Finnish (NFE) AF: 0.0860 AC: 95516 AN: 1111272

Other (OTH) AF: 0.0721 AC: 4353 AN: 60350

GnomAD4 genome AF: 0.0639 AC: 9717 AN: 152176 Hom.: 415 Cov.: 32 AF XY: 0.0631 AC XY: 4695 AN XY: 74390

African (AFR) AF: 0.0262 AC: 1087 AN: 41534

American (AMR) AF: 0.0413 AC: 631 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0648 AC: 225 AN: 3470

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5174

South Asian (SAS) AF: 0.0641 AC: 309 AN: 4820

European-Finnish (FIN) AF: 0.113 AC: 1195 AN: 10578

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0884 AC: 6011 AN: 67990

Other (OTH) AF: 0.0626 AC: 132 AN: 2110

Alfa AF: 0.0761 Hom.: 1386

Bravo AF: 0.0568

TwinsUK AF: 0.0866 AC: 321

ALSPAC AF: 0.0815 AC: 314

ESP6500AA AF: 0.0286 AC: 106

ESP6500EA AF: 0.0815 AC: 668

ExAC AF: 0.0680 AC: 8215

Asia WGS AF: 0.0470 AC: 163 AN: 3478

EpiCase AF: 0.0855

EpiControl AF: 0.0825

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 10, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 2C Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.070
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.084
DANN	Benign	0.87
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.52	.;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.2
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.090	.;N
REVEL	Benign	0.0060
Sift	Benign	0.18	.;T
Sift4G	Benign	0.23	.;T
Polyphen		0.010	B;B
Vest4		0.012
MPC		0.042
ClinPred		0.00055	T
GERP RS		-3.0
Varity_R		0.029
gMVP		0.17
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13157270; hg19: chr5-90012379; COSMIC: COSV101316708; COSMIC: COSV101316708;