chr2-135135802-A-G

Variant names:

Variant summary

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

The NM_012233.3(RAB3GAP1):c.1793A>G(p.Asn598Ser) variant causes a missense change. The variant allele was found at a frequency of 0.147 in 1,613,824 control chromosomes in the GnomAD database, including 24,629 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 2387 hom., cov: 32)

Exomes 𝑓: 0.15 ( 22242 hom. )

Consequence

RAB3GAP1
NM_012233.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 5.03

Publications

43 publications found

Variant links:

Genes affected

RAB3GAP1 (HGNC:17063): (RAB3 GTPase activating protein catalytic subunit 1) This gene encodes the catalytic subunit of a Rab GTPase activating protein. The encoded protein forms a heterodimer with a non-catalytic subunit to specifically regulate the activity of members of the Rab3 subfamily of small G proteins. This protein mediates the hydrolysis of GTP bound Rab3 to the GDP bound form. Mutations in this gene are associated with Warburg micro syndrome. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Feb 2010]

RAB3GAP1 Gene-Disease associations (from GenCC):

Warburg micro syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Warburg micro syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
cataract-intellectual disability-hypogonadism syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RAB3GAP1 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=0.003854096).

BP6

Variant 2-135135802-A-G is Benign according to our data. Variant chr2-135135802-A-G is described in ClinVar as Benign. ClinVar VariationId is 130064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB3GAP1	NM_012233.3 link	c.1793A>G	p.Asn598Ser	missense_variant	Exon 17 of 24	ENST00000264158.13	NP_036365.1	Q15042-1B9A6J2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB3GAP1	ENST00000264158.13 link	c.1793A>G	p.Asn598Ser	missense_variant	Exon 17 of 24	1	NM_012233.3	ENSP00000264158.8		Q15042-1

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

22013

AN:

152076

Hom.:

2384

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0371

Gnomad AMI

AF:

0.143

Gnomad AMR

AF:

0.229

Gnomad ASJ

AF:

0.400

Gnomad EAS

AF:

0.382

Gnomad SAS

AF:

0.294

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.147

Gnomad OTH

AF:

0.204

GnomAD2 exomes

AF:

0.204

AC:

51342

AN:

251228

AF XY:

0.211

show subpopulations

Gnomad AFR exome

AF:

0.0327

Gnomad AMR exome

AF:

0.249

Gnomad ASJ exome

AF:

0.397

Gnomad EAS exome

AF:

0.389

Gnomad FIN exome

AF:

0.144

Gnomad NFE exome

AF:

0.154

Gnomad OTH exome

AF:

0.237

GnomAD4 exome

AF:

0.147

AC:

214878

AN:

1461630

Hom.:

22242

Cov.:

AF XY:

0.154

AC XY:

112059

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.0359

AC:

1202

AN:

33474

American (AMR)

AF:

0.244

AC:

10892

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.392

AC:

10238

AN:

26132

East Asian (EAS)

AF:

0.404

AC:

16023

AN:

39696

South Asian (SAS)

AF:

0.287

AC:

24760

AN:

86252

European-Finnish (FIN)

AF:

0.148

AC:

7879

AN:

53414

Middle Eastern (MID)

AF:

0.345

AC:

1990

AN:

5766

European-Non Finnish (NFE)

AF:

0.118

AC:

130815

AN:

1111798

Other (OTH)

AF:

0.183

AC:

11079

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

10460

20921

31381

41842

52302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4518

9036

13554

18072

22590

<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:

0.145

AC:

22033

AN:

152194

Hom.:

2387

Cov.:

AF XY:

0.151

AC XY:

11252

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0370

AC:

1539

AN:

41558

American (AMR)

AF:

0.229

AC:

3506

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.400

AC:

1388

AN:

3468

East Asian (EAS)

AF:

0.383

AC:

1975

AN:

5160

South Asian (SAS)

AF:

0.294

AC:

1421

AN:

4826

European-Finnish (FIN)

AF:

0.144

AC:

1526

AN:

10590

Middle Eastern (MID)

AF:

0.347

AC:

102

AN:

294

European-Non Finnish (NFE)

AF:

0.147

AC:

10004

AN:

67990

Other (OTH)

AF:

0.209

AC:

442

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

860

1720

2581

3441

4301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

254

508

762

1016

1270

<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:

0.166

Hom.:

8451

Bravo

AF:

0.144

TwinsUK

AF:

0.108

AC:

399

ALSPAC

AF:

0.111

AC:

427

ESP6500AA

AF:

0.0313

AC:

138

ESP6500EA

AF:

0.154

AC:

1324

ExAC

AF:

0.201

AC:

24339

Asia WGS

AF:

0.321

AC:

1117

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

May 07, 2018

Athena Diagnostics

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Warburg micro syndrome 1

Benign:3

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Martsolf syndrome 2

Benign:1

Nov 07, 2021

Genome-Nilou Lab

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

0.067

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.051

T;.;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.066

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.86

D;D;D

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.92

L;L;.

PhyloP100

5.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.60

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.26

T;T;T

Sift4G

Benign

0.82

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.073

MPC

0.18

ClinPred

0.010

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.031

gMVP

0.084

Mutation Taster

=100/0

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