NM_012233.3:c.1006C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_012233.3(RAB3GAP1):c.1006C>T(p.Arg336Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 1,611,028 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 35 hom. )

Consequence

RAB3GAP1
NM_012233.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:7

Conservation

PhyloP100: 2.61

Publications

9 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: G2P, Labcorp Genetics (formerly Invitae)
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=0.010591298).

BP6

Variant 2-135130027-C-T is Benign according to our data. Variant chr2-135130027-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0041 (619/151110) while in subpopulation NFE AF = 0.00637 (432/67860). AF 95% confidence interval is 0.00587. There are 2 homozygotes in GnomAd4. There are 306 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012233.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB3GAP1	NM_012233.3	MANE Select	c.1006C>T	p.Arg336Cys	missense	Exon 12 of 24	NP_036365.1	B9A6J2
	RAB3GAP1	NM_001172435.2		c.1006C>T	p.Arg336Cys	missense	Exon 12 of 25	NP_001165906.1	Q15042-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAB3GAP1	ENST00000264158.13	TSL:1 MANE Select	c.1006C>T	p.Arg336Cys	missense	Exon 12 of 24	ENSP00000264158.8	Q15042-1
RAB3GAP1	ENST00000442034.5	TSL:1	c.1006C>T	p.Arg336Cys	missense	Exon 12 of 25	ENSP00000411418.1	Q15042-3
RAB3GAP1	ENST00000970735.1		c.1009C>T	p.Arg337Cys	missense	Exon 12 of 24	ENSP00000640794.1

Frequencies

GnomAD3 genomes

AF:

0.00410

AC:

619

AN:

150992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00110

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00375

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00292

Gnomad FIN

AF:

0.00430

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00637

Gnomad OTH

AF:

0.00193

GnomAD2 exomes

AF:

0.00430

AC:

1079

AN:

250700

AF XY:

0.00433

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.00368

Gnomad ASJ exome

AF:

0.00467

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.00500

Gnomad NFE exome

AF:

0.00603

Gnomad OTH exome

AF:

0.00507

GnomAD4 exome

AF:

0.00422

AC:

6164

AN:

1459918

Hom.:

Cov.:

AF XY:

0.00446

AC XY:

3237

AN XY:

726158

show subpopulations

African (AFR)

AF:

0.000509

AC:

AN:

33430

American (AMR)

AF:

0.00358

AC:

160

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00625

AC:

163

AN:

26072

East Asian (EAS)

AF:

0.000152

AC:

AN:

39594

South Asian (SAS)

AF:

0.00216

AC:

185

AN:

85814

European-Finnish (FIN)

AF:

0.00592

AC:

316

AN:

53376

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00457

AC:

5078

AN:

1110888

Other (OTH)

AF:

0.00385

AC:

232

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

287

573

860

1146

1433

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

296

444

592

740

<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:

0.00410

AC:

619

AN:

151110

Hom.:

Cov.:

AF XY:

0.00415

AC XY:

306

AN XY:

73668

show subpopulations

African (AFR)

AF:

0.00109

AC:

AN:

41098

American (AMR)

AF:

0.00375

AC:

AN:

15200

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00292

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00430

AC:

AN:

10242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00637

AC:

432

AN:

67860

Other (OTH)

AF:

0.00191

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

105

140

175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00434

Hom.:

Bravo

AF:

0.00353

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00663

AC:

ExAC

AF:

0.00447

AC:

543

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00645

EpiControl

AF:

0.00617

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Amenorrhea (1)

not specified (1)

Warburg micro syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.36

Eigen

Benign

-0.090

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.014

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-0.70

PhyloP100

2.6

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.0

REVEL

Benign

0.17

Sift

Benign

0.11

Sift4G

Benign

0.25

Polyphen

0.0060

Vest4

0.42

MVP

0.78

MPC

0.30

ClinPred

0.013

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.28

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over