chr1-220151373-T-C

Position:

chr1-220151373-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_012414.4(RAB3GAP2):c.4060A>G(p.Ile1354Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000528 in 1,614,184 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 1 hom. )

Consequence

RAB3GAP2
NM_012414.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 2.69

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 links:

RAB3GAP2 (HGNC:):

RAB3GAP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004238844).

BP6

Variant 1-220151373-T-C is Benign according to our data. Variant chr1-220151373-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211989.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1, Benign=1}. Variant chr1-220151373-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0017 (259/152320) while in subpopulation AFR AF= 0.0051 (212/41566). AF 95% confidence interval is 0.00454. There are 1 homozygotes in gnomad4. There are 127 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB3GAP2	NM_012414.4 linkuse as main transcript	c.4060A>G	p.Ile1354Val	missense_variant	35/35	ENST00000358951.7	NP_036546.2	Q9H2M9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB3GAP2	ENST00000358951.7 linkuse as main transcript	c.4060A>G	p.Ile1354Val	missense_variant	35/35	1	NM_012414.4	ENSP00000351832.2		Q9H2M9-1

Frequencies

GnomAD3 genomes

AF:

0.00170

AC:

259

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00512

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.000787

AC:

196

AN:

249070

Hom.:

AF XY:

0.000630

AC XY:

AN XY:

134820

show subpopulations

Gnomad AFR exome

AF:

0.00486

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000359

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000406

AC:

593

AN:

1461864

Hom.:

Cov.:

AF XY:

0.000400

AC XY:

291

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00520

Gnomad4 AMR exome

AF:

0.00174

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000215

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.00170

AC:

259

AN:

152320

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

127

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00510

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.000534

Hom.:

Bravo

AF:

0.00172

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000725

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 22, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 04, 2015	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	RAB3GAP2: BP4 -

Warburg micro syndrome 2

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. -

Martsolf syndrome;C3280214:Warburg micro syndrome 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Martsolf syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

RAB3GAP2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2021

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.018

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.78

M_CAP

Benign

0.0052

MetaRNN

Benign

0.0042

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.47

REVEL

Benign

0.039

Sift

Benign

0.59

Sift4G

Benign

0.16

Polyphen

0.0030

Vest4

0.12

MVP

0.23

MPC

0.12

ClinPred

0.013

GERP RS

3.5

Varity_R

0.024

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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