chr2-135130027-C-T

Position:

chr2-135130027-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/21 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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB3GAP1	NM_012233.3 linkuse as main transcript	c.1006C>T	p.Arg336Cys	missense_variant	12/24	ENST00000264158.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB3GAP1	ENST00000264158.13 linkuse as main transcript	c.1006C>T	p.Arg336Cys	missense_variant	12/24	1	NM_012233.3	A1	Q15042-1

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

GnomAD3 exomes

AF:

0.00430

AC:

1079

AN:

250700

Hom.:

AF XY:

0.00433

AC XY:

587

AN XY:

135484

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 SAS exome

AF:

0.00231

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

Gnomad4 AFR exome

AF:

0.000509

Gnomad4 AMR exome

AF:

0.00358

Gnomad4 ASJ exome

AF:

0.00625

Gnomad4 EAS exome

AF:

0.000152

Gnomad4 SAS exome

AF:

0.00216

Gnomad4 FIN exome

AF:

0.00592

Gnomad4 NFE exome

AF:

0.00457

Gnomad4 OTH exome

AF:

0.00385

GnomAD4 genome

AF:

0.00410

AC:

619

AN:

151110

Hom.:

Cov.:

AF XY:

0.00415

AC XY:

306

AN XY:

73668

show subpopulations

Gnomad4 AFR

AF:

0.00109

Gnomad4 AMR

AF:

0.00375

Gnomad4 ASJ

AF:

0.00663

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00292

Gnomad4 FIN

AF:

0.00430

Gnomad4 NFE

AF:

0.00637

Gnomad4 OTH

AF:

0.00191

Alfa

AF:

0.00579

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

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 29, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	RAB3GAP1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2020	This variant is associated with the following publications: (PMID: 29924831) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 06, 2018	- -

Amenorrhea

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Mar 08, 2021

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 20, 2016

- -

Warburg micro syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.36

T;.;.

Eigen

Benign

-0.090

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-0.70

N;N;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.25

T;T;T

Polyphen

0.0060

B;.;.

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

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

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