NM_032119.4:c.3279G>T

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.3279G>T(p.Leu1093Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 1,609,430 control chromosomes in the GnomAD database, including 366,496 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L1093L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.74 ( 42871 hom., cov: 32)

Exomes 𝑓: 0.66 ( 323625 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.293

Publications

40 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=8.170927E-7).

BP6

Variant 5-90647754-G-T is Benign according to our data. Variant chr5-90647754-G-T is described in ClinVar as Benign. ClinVar VariationId is 46313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.903 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4 link	c.3279G>T	p.Leu1093Phe	missense_variant	Exon 17 of 90	ENST00000405460.9	NP_115495.3	Q8WXG9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADGRV1	ENST00000405460.9 link	c.3279G>T	p.Leu1093Phe	missense_variant	Exon 17 of 90	1	NM_032119.4	ENSP00000384582.2	Q8WXG9-1
ADGRV1	ENST00000640403.1 link	c.582G>T	p.Leu194Phe	missense_variant	Exon 7 of 29	5		ENSP00000492531.1	A0A1W2PRC7
ADGRV1	ENST00000504142.2 link	n.2045G>T		non_coding_transcript_exon_variant	Exon 11 of 14	5
ADGRV1	ENST00000639676.1 link	n.877G>T		non_coding_transcript_exon_variant	Exon 5 of 11	5

Frequencies

GnomAD3 genomes

AF:

0.741

AC:

112562

AN:

151944

Hom.:

42800

Cov.:

show subpopulations

Gnomad AFR

AF:

0.910

Gnomad AMI

AF:

0.716

Gnomad AMR

AF:

0.780

Gnomad ASJ

AF:

0.671

Gnomad EAS

AF:

0.812

Gnomad SAS

AF:

0.727

Gnomad FIN

AF:

0.662

Gnomad MID

AF:

0.687

Gnomad NFE

AF:

0.640

Gnomad OTH

AF:

0.748

GnomAD2 exomes

AF:

0.711

AC:

176353

AN:

247886

AF XY:

0.702

show subpopulations

Gnomad AFR exome

AF:

0.915

Gnomad AMR exome

AF:

0.827

Gnomad ASJ exome

AF:

0.669

Gnomad EAS exome

AF:

0.801

Gnomad FIN exome

AF:

0.670

Gnomad NFE exome

AF:

0.643

Gnomad OTH exome

AF:

0.704

GnomAD4 exome

AF:

0.663

AC:

966248

AN:

1457368

Hom.:

323625

Cov.:

AF XY:

0.663

AC XY:

480374

AN XY:

724988

show subpopulations

African (AFR)

AF:

0.916

AC:

30555

AN:

33356

American (AMR)

AF:

0.823

AC:

36712

AN:

44610

Ashkenazi Jewish (ASJ)

AF:

0.670

AC:

17479

AN:

26084

East Asian (EAS)

AF:

0.817

AC:

32402

AN:

39672

South Asian (SAS)

AF:

0.719

AC:

61847

AN:

86032

European-Finnish (FIN)

AF:

0.668

AC:

35478

AN:

53140

Middle Eastern (MID)

AF:

0.698

AC:

4015

AN:

5756

European-Non Finnish (NFE)

AF:

0.637

AC:

706228

AN:

1108518

Other (OTH)

AF:

0.690

AC:

41532

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

14589

29178

43768

58357

72946

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18826

37652

56478

75304

94130

<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:

0.741

AC:

112688

AN:

152062

Hom.:

42871

Cov.:

AF XY:

0.744

AC XY:

55255

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.911

AC:

37802

AN:

41514

American (AMR)

AF:

0.780

AC:

11920

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.671

AC:

2326

AN:

3466

East Asian (EAS)

AF:

0.813

AC:

4200

AN:

5166

South Asian (SAS)

AF:

0.725

AC:

3492

AN:

4818

European-Finnish (FIN)

AF:

0.662

AC:

6981

AN:

10540

Middle Eastern (MID)

AF:

0.687

AC:

202

AN:

294

European-Non Finnish (NFE)

AF:

0.640

AC:

43524

AN:

67966

Other (OTH)

AF:

0.752

AC:

1588

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1404

2808

4213

5617

7021

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

838

1676

2514

3352

4190

<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:

0.676

Hom.:

154673

Bravo

AF:

0.761

TwinsUK

AF:

0.629

AC:

2332

ALSPAC

AF:

0.649

AC:

2502

ESP6500AA

AF:

0.912

AC:

3338

ESP6500EA

AF:

0.645

AC:

5258

ExAC

AF:

0.709

AC:

85636

Asia WGS

AF:

0.808

AC:

2809

AN:

3478

EpiCase

AF:

0.652

EpiControl

AF:

0.651

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Feb 02, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Caucasian frequency = 4255/6556 (ESP data) -

Jul 21, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2C

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.035

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.047

T;T;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.17

.;T;T

MetaRNN

Benign

8.2e-7

T;T;T

MetaSVM

Benign

-0.97

PhyloP100

0.29

PrimateAI

Uncertain

0.55

PROVEAN

Benign

2.8

.;N;.

REVEL

Benign

0.061

Sift

Benign

1.0

.;T;.

Sift4G

Benign

1.0

.;T;.

Polyphen

0.0

B;B;.

Vest4

0.028

MutPred

0.52

Gain of catalytic residue at L1093 (P = 0.2302);Gain of catalytic residue at L1093 (P = 0.2302);.;

MPC

0.050

ClinPred

0.00040

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.065

gMVP

0.29

Mutation Taster

=95/5

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