rs10037067

Variant names:

• chr5-90690065-A-G
• rs10037067
• NM_032119.4:c.6695A>G

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.6695A>G​(p.Tyr2232Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,545,226 control chromosomes in the GnomAD database, including 94,105 homozygotes. In-silico tool predicts 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. Y2232R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.34 (9004 hom., cov: 31)
  • Exomes 𝑓: 0.34 (85101 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.16
• Publications: 42 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=5.3060055E-4).
• BP6: Variant 5-90690065-A-G is Benign according to our data. Variant chr5-90690065-A-G is described in ClinVar as Benign. ClinVar VariationId is 46356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.6695A>G	p.Tyr2232Cys	missense_variant	Exon 30 of 90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.6695A>G	p.Tyr2232Cys	missense_variant	Exon 30 of 90	1	NM_032119.4	ENSP00000384582.2

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51372 AN: 151848 Hom.: 8980 Cov.: 31

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.481

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.280

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.369

GnomAD2 exomes AF: 0.365 AC: 66647 AN: 182748 AF XY: 0.356

Gnomad AFR exome AF: 0.291

Gnomad AMR exome AF: 0.574

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.365

Gnomad FIN exome AF: 0.333

Gnomad NFE exome AF: 0.335

Gnomad OTH exome AF: 0.360

GnomAD4 exome AF: 0.345 AC: 480345 AN: 1393260 Hom.: 85101 Cov.: 26 AF XY: 0.343 AC XY: 236610 AN XY: 690630

African (AFR) AF: 0.281 AC: 9029 AN: 32154

American (AMR) AF: 0.560 AC: 20915 AN: 37318

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 6911 AN: 25214

East Asian (EAS) AF: 0.433 AC: 16357 AN: 37784

South Asian (SAS) AF: 0.327 AC: 26296 AN: 80452

European-Finnish (FIN) AF: 0.339 AC: 17243 AN: 50838

Middle Eastern (MID) AF: 0.280 AC: 1586 AN: 5674

European-Non Finnish (NFE) AF: 0.340 AC: 362333 AN: 1065844

Other (OTH) AF: 0.339 AC: 19675 AN: 57982

GnomAD4 genome AF: 0.338 AC: 51426 AN: 151966 Hom.: 9004 Cov.: 31 AF XY: 0.341 AC XY: 25321 AN XY: 74284

African (AFR) AF: 0.293 AC: 12155 AN: 41450

American (AMR) AF: 0.482 AC: 7355 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 968 AN: 3472

East Asian (EAS) AF: 0.386 AC: 1992 AN: 5162

South Asian (SAS) AF: 0.322 AC: 1551 AN: 4816

European-Finnish (FIN) AF: 0.334 AC: 3525 AN: 10564

Middle Eastern (MID) AF: 0.288 AC: 84 AN: 292

European-Non Finnish (NFE) AF: 0.334 AC: 22706 AN: 67928

Other (OTH) AF: 0.364 AC: 767 AN: 2108

Alfa AF: 0.341 Hom.: 35598

Bravo AF: 0.353

TwinsUK AF: 0.333 AC: 1233

ALSPAC AF: 0.351 AC: 1351

ESP6500AA AF: 0.293 AC: 1070

ESP6500EA AF: 0.329 AC: 2688

ExAC AF: 0.309 AC: 35600

Asia WGS AF: 0.351 AC: 1221 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 23, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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. -

Febrile seizures, familial, 4;C2931213:Usher syndrome type 2C Benign:1

Aug 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	.;D;D
MetaRNN	Benign	0.00053	T;T;T
MetaSVM	Benign	-0.91	T
PhyloP100		2.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.3	.;D;.
REVEL	Benign	0.17
Sift	Uncertain	0.0070	.;D;.
Sift4G	Uncertain	0.0020	.;D;.
Polyphen		1.0	D;D;.
Vest4		0.24
MPC		0.33
ClinPred		0.027	T
GERP RS		2.8
Varity_R		0.38
gMVP		0.73
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: rs10037067; hg19: chr5-89985882; COSMIC: COSV67985306; COSMIC: COSV67985306;