5-90756472-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032119.4(ADGRV1):c.11599G>A(p.Glu3867Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 1,529,114 control chromosomes in the GnomAD database, including 94,980 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 7609 hom., cov: 32)

Exomes 𝑓: 0.35 ( 87371 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.97

Publications

35 publications found

Variant links:

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

ADGRV1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=8.4617734E-4).

BP6

Variant 5-90756472-G-A is Benign according to our data. Variant chr5-90756472-G-A is described in ClinVar as Benign. ClinVar VariationId is 46257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4 link	c.11599G>A	p.Glu3867Lys	missense_variant	Exon 56 of 90	ENST00000405460.9	NP_115495.3	Q8WXG9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9 link	c.11599G>A	p.Glu3867Lys	missense_variant	Exon 56 of 90	1	NM_032119.4	ENSP00000384582.2		Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.283

AC:

43032

AN:

151934

Hom.:

7598

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0770

Gnomad AMI

AF:

0.263

Gnomad AMR

AF:

0.466

Gnomad ASJ

AF:

0.250

Gnomad EAS

AF:

0.479

Gnomad SAS

AF:

0.305

Gnomad FIN

AF:

0.342

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.343

Gnomad OTH

AF:

0.314

GnomAD2 exomes

AF:

0.344

AC:

74321

AN:

216116

AF XY:

0.339

show subpopulations

Gnomad AFR exome

AF:

0.0659

Gnomad AMR exome

AF:

0.568

Gnomad ASJ exome

AF:

0.239

Gnomad EAS exome

AF:

0.433

Gnomad FIN exome

AF:

0.342

Gnomad NFE exome

AF:

0.332

Gnomad OTH exome

AF:

0.341

GnomAD4 exome

AF:

0.348

AC:

478908

AN:

1377062

Hom.:

87371

Cov.:

AF XY:

0.345

AC XY:

234497

AN XY:

680584

show subpopulations

African (AFR)

AF:

0.0641

AC:

1952

AN:

30434

American (AMR)

AF:

0.554

AC:

20051

AN:

36204

Ashkenazi Jewish (ASJ)

AF:

0.246

AC:

5899

AN:

23960

East Asian (EAS)

AF:

0.498

AC:

18561

AN:

37260

South Asian (SAS)

AF:

0.289

AC:

19984

AN:

69114

European-Finnish (FIN)

AF:

0.346

AC:

17630

AN:

50986

Middle Eastern (MID)

AF:

0.250

AC:

1370

AN:

5470

European-Non Finnish (NFE)

AF:

0.351

AC:

374537

AN:

1066892

Other (OTH)

AF:

0.334

AC:

18924

AN:

56742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

13566

27132

40699

54265

67831

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12476

24952

37428

49904

62380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.283

AC:

43041

AN:

152052

Hom.:

7609

Cov.:

AF XY:

0.287

AC XY:

21314

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0768

AC:

3190

AN:

41524

American (AMR)

AF:

0.467

AC:

7125

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.250

AC:

866

AN:

3468

East Asian (EAS)

AF:

0.478

AC:

2473

AN:

5170

South Asian (SAS)

AF:

0.305

AC:

1468

AN:

4814

European-Finnish (FIN)

AF:

0.342

AC:

3605

AN:

10544

Middle Eastern (MID)

AF:

0.265

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.343

AC:

23339

AN:

67952

Other (OTH)

AF:

0.310

AC:

657

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1398

2796

4193

5591

6989

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

430

860

1290

1720

2150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.321

Hom.:

20905

Bravo

AF:

0.287

TwinsUK

AF:

0.349

AC:

1294

ALSPAC

AF:

0.363

AC:

1400

ESP6500AA

AF:

0.0832

AC:

317

ESP6500EA

AF:

0.331

AC:

2735

ExAC

AF:

0.345

AC:

41720

Asia WGS

AF:

0.377

AC:

1312

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Nov 22, 2015

Eurofins Ntd Llc (ga)

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

- -

Mar 23, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

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

0.15

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.14

T;T

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.88

.;D

MetaRNN

Benign

0.00085

T;T

MetaSVM

Benign

-0.82

PhyloP100

3.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.5

.;N

REVEL

Benign

0.076

Sift

Benign

0.22

.;T

Sift4G

Benign

0.25

.;T

Polyphen

0.50

P;P

Vest4

0.14

MPC

0.057

ClinPred

0.0091

GERP RS

5.8

Varity_R

0.22

gMVP

0.68

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over