rs12045447

Variant names:

Variant summary

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

The NM_012414.4(RAB3GAP2):c.2587A>G(p.Thr863Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 1,613,656 control chromosomes in the GnomAD database, including 1,366 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 215 hom., cov: 32)

Exomes 𝑓: 0.036 ( 1151 hom. )

Consequence

RAB3GAP2
NM_012414.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.601

Publications

19 publications found

Variant links:

Genes affected

RAB3GAP2 (HGNC:17168): (RAB3 GTPase activating non-catalytic protein subunit 2) The protein encoded by this gene belongs to the RAB3 protein family, members of which are involved in regulated exocytosis of neurotransmitters and hormones. This protein forms the Rab3 GTPase-activating complex with RAB3GAP1, where it constitutes the regulatory subunit, whereas the latter functions as the catalytic subunit. This gene has the highest level of expression in the brain, consistent with it having a key role in neurodevelopment. Mutations in this gene are associated with Martsolf syndrome.[provided by RefSeq, Oct 2009]

RAB3GAP2 Gene-Disease associations (from GenCC):

Martsolf syndrome 1
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
RAB18 deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
Warburg micro syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Warburg micro syndrome 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
autosomal recessive spastic paraplegia type 69
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
cataract-intellectual disability-hypogonadism syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RAB3GAP2 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=0.0012030005).

BP6

Variant 1-220171111-T-C is Benign according to our data. Variant chr1-220171111-T-C is described in ClinVar as Benign. ClinVar VariationId is 130078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB3GAP2	NM_012414.4 link	c.2587A>G	p.Thr863Ala	missense_variant	Exon 24 of 35	ENST00000358951.7	NP_036546.2	Q9H2M9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB3GAP2	ENST00000358951.7 link	c.2587A>G	p.Thr863Ala	missense_variant	Exon 24 of 35	1	NM_012414.4	ENSP00000351832.2		Q9H2M9-1

Frequencies

GnomAD3 genomes

AF:

0.0471

AC:

7159

AN:

152100

Hom.:

210

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0793

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0360

Gnomad ASJ

AF:

0.0890

Gnomad EAS

AF:

0.0359

Gnomad SAS

AF:

0.0433

Gnomad FIN

AF:

0.00791

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0353

Gnomad OTH

AF:

0.0506

GnomAD2 exomes

AF:

0.0384

AC:

9634

AN:

250970

AF XY:

0.0386

show subpopulations

Gnomad AFR exome

AF:

0.0778

Gnomad AMR exome

AF:

0.0262

Gnomad ASJ exome

AF:

0.0778

Gnomad EAS exome

AF:

0.0411

Gnomad FIN exome

AF:

0.00859

Gnomad NFE exome

AF:

0.0379

Gnomad OTH exome

AF:

0.0478

GnomAD4 exome

AF:

0.0356

AC:

51955

AN:

1461438

Hom.:

1151

Cov.:

AF XY:

0.0359

AC XY:

26120

AN XY:

727056

show subpopulations

African (AFR)

AF:

0.0842

AC:

2817

AN:

33460

American (AMR)

AF:

0.0277

AC:

1237

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0772

AC:

2017

AN:

26124

East Asian (EAS)

AF:

0.0359

AC:

1425

AN:

39696

South Asian (SAS)

AF:

0.0380

AC:

3281

AN:

86246

European-Finnish (FIN)

AF:

0.00959

AC:

512

AN:

53416

Middle Eastern (MID)

AF:

0.0679

AC:

391

AN:

5760

European-Non Finnish (NFE)

AF:

0.0338

AC:

37518

AN:

1111644

Other (OTH)

AF:

0.0457

AC:

2757

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

2393

4786

7179

9572

11965

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1444

2888

4332

5776

7220

<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:

0.0472

AC:

7188

AN:

152218

Hom.:

215

Cov.:

AF XY:

0.0458

AC XY:

3408

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0797

AC:

3307

AN:

41518

American (AMR)

AF:

0.0360

AC:

550

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0890

AC:

309

AN:

3470

East Asian (EAS)

AF:

0.0361

AC:

187

AN:

5174

South Asian (SAS)

AF:

0.0429

AC:

207

AN:

4820

European-Finnish (FIN)

AF:

0.00791

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0353

AC:

2401

AN:

68008

Other (OTH)

AF:

0.0529

AC:

112

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

346

692

1039

1385

1731

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0407

Hom.:

542

Bravo

AF:

0.0497

TwinsUK

AF:

0.0254

AC:

ALSPAC

AF:

0.0374

AC:

144

ESP6500AA

AF:

0.0749

AC:

330

ESP6500EA

AF:

0.0380

AC:

327

ExAC

AF:

0.0401

AC:

4872

Asia WGS

AF:

0.0470

AC:

163

AN:

3478

EpiCase

AF:

0.0419

EpiControl

AF:

0.0437

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

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

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. -

Apr 28, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Warburg micro syndrome 2

Benign:2

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. -

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Martsolf syndrome

Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Martsolf syndrome;C3280214:Warburg micro syndrome 2

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.024

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0012

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

0.60

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.92

REVEL

Benign

0.056

Sift

Benign

0.75

Sift4G

Benign

0.58

Polyphen

0.0020

Vest4

0.015

MPC

0.14

ClinPred

0.00098

GERP RS

0.66

Varity_R

0.034

gMVP

0.19

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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