2-135153852-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_012233.3(RAB3GAP1):c.2265T>C(p.Phe755Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 1,613,426 control chromosomes in the GnomAD database, including 150,350 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 28389 hom., cov: 32)

Exomes 𝑓: 0.34 ( 121961 hom. )

Consequence

RAB3GAP1
NM_012233.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.154

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 links:

ZRANB3 (HGNC:25249): (zinc finger RANBP2-type containing 3) Enables ATP-dependent DNA/DNA annealing activity; K63-linked polyubiquitin modification-dependent protein binding activity; and endodeoxyribonuclease activity. Involved in several processes, including DNA metabolic process; DNA rewinding; and negative regulation of DNA recombination. Located in nuclear replication fork and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ZRANB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 2-135153852-T-C is Benign according to our data. Variant chr2-135153852-T-C is described in ClinVar as [Benign]. Clinvar id is 130067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-135153852-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.154 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB3GAP1	NM_012233.3 link	c.2265T>C	p.Phe755Phe	synonymous_variant	Exon 19 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.2265T>C	p.Phe755Phe	synonymous_variant	Exon 19 of 24	1	NM_012233.3	ENSP00000264158.8		Q15042-1

Frequencies

GnomAD3 genomes

AF:

0.543

AC:

82449

AN:

151978

Hom.:

28324

Cov.:

show subpopulations

Gnomad AFR

AF:

0.868

Gnomad AMI

AF:

0.222

Gnomad AMR

AF:

0.669

Gnomad ASJ

AF:

0.715

Gnomad EAS

AF:

0.996

Gnomad SAS

AF:

0.730

Gnomad FIN

AF:

0.312

Gnomad MID

AF:

0.690

Gnomad NFE

AF:

0.297

Gnomad OTH

AF:

0.594

GnomAD3 exomes

AF:

0.520

AC:

130582

AN:

250934

Hom.:

43378

AF XY:

0.512

AC XY:

69433

AN XY:

135624

show subpopulations

Gnomad AFR exome

AF:

0.878

Gnomad AMR exome

AF:

0.727

Gnomad ASJ exome

AF:

0.717

Gnomad EAS exome

AF:

0.999

Gnomad SAS exome

AF:

0.687

Gnomad FIN exome

AF:

0.313

Gnomad NFE exome

AF:

0.306

Gnomad OTH exome

AF:

0.512

GnomAD4 exome

AF:

0.340

AC:

496730

AN:

1461330

Hom.:

121961

Cov.:

AF XY:

0.352

AC XY:

256117

AN XY:

726952

show subpopulations

Gnomad4 AFR exome

AF:

0.897

Gnomad4 AMR exome

AF:

0.718

Gnomad4 ASJ exome

AF:

0.717

Gnomad4 EAS exome

AF:

0.999

Gnomad4 SAS exome

AF:

0.678

Gnomad4 FIN exome

AF:

0.312

Gnomad4 NFE exome

AF:

0.244

Gnomad4 OTH exome

AF:

0.434

GnomAD4 genome

AF:

0.543

AC:

82579

AN:

152096

Hom.:

28389

Cov.:

AF XY:

0.555

AC XY:

41289

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.869

Gnomad4 AMR

AF:

0.669

Gnomad4 ASJ

AF:

0.715

Gnomad4 EAS

AF:

0.996

Gnomad4 SAS

AF:

0.729

Gnomad4 FIN

AF:

0.312

Gnomad4 NFE

AF:

0.297

Gnomad4 OTH

AF:

0.598

Alfa

AF:

0.396

Hom.:

15359

Bravo

AF:

0.582

Asia WGS

AF:

0.882

AC:

3063

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

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. -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

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

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

- -

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

- -

Warburg micro syndrome 1

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Warburg micro syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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

BayesDel_noAF

Benign

-0.52

CADD

Benign

5.0

DANN

Benign

0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over