rs61748693

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_012233.3(RAB3GAP1):c.2463C>T(p.Phe821Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00812 in 1,612,868 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 14 hom., cov: 33)

Exomes 𝑓: 0.0081 ( 96 hom. )

Consequence

RAB3GAP1
NM_012233.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.359

Publications

3 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 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 was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 2-135162824-C-T is Benign according to our data. Variant chr2-135162824-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.359 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00814 (1239/152286) while in subpopulation NFE AF = 0.0105 (715/68032). AF 95% confidence interval is 0.00987. There are 14 homozygotes in GnomAd4. There are 631 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB3GAP1	NM_012233.3 link	c.2463C>T	p.Phe821Phe	synonymous_variant	Exon 21 of 24	ENST00000264158.13	NP_036365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB3GAP1	ENST00000264158.13 link	c.2463C>T	p.Phe821Phe	synonymous_variant	Exon 21 of 24	1	NM_012233.3	ENSP00000264158.8

Frequencies

GnomAD3 genomes

AF:

0.00814

AC:

1239

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00982

Gnomad ASJ

AF:

0.0403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.0113

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0105

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.00937

AC:

2350

AN:

250708

AF XY:

0.00984

show subpopulations

Gnomad AFR exome

AF:

0.00101

Gnomad AMR exome

AF:

0.00813

Gnomad ASJ exome

AF:

0.0413

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00989

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.0123

GnomAD4 exome

AF:

0.00811

AC:

11850

AN:

1460582

Hom.:

Cov.:

AF XY:

0.00821

AC XY:

5965

AN XY:

726696

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

33454

American (AMR)

AF:

0.00881

AC:

394

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0403

AC:

1053

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00212

AC:

183

AN:

86220

European-Finnish (FIN)

AF:

0.0103

AC:

549

AN:

53416

Middle Eastern (MID)

AF:

0.0125

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00809

AC:

8988

AN:

1110846

Other (OTH)

AF:

0.00951

AC:

574

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

666

1331

1997

2662

3328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

306

612

918

1224

1530

<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:

0.00814

AC:

1239

AN:

152286

Hom.:

Cov.:

AF XY:

0.00847

AC XY:

631

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00188

AC:

AN:

41552

American (AMR)

AF:

0.00981

AC:

150

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0403

AC:

140

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00249

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0113

AC:

120

AN:

10610

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0105

AC:

715

AN:

68032

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

116

174

232

290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00934

Hom.:

Bravo

AF:

0.00800

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0148

EpiControl

AF:

0.0164

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jun 24, 2015

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 08, 2015

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. -

Jul 30, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RAB3GAP1: BP4, BP7, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

RAB3GAP1-related disorder

Benign:1

Apr 16, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Warburg micro syndrome 1

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

7.0

(source)

DANN

Benign

0.75

PhyloP100

0.36

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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