rs116775947

Positions:

• chr2-135126596-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012233.3(RAB3GAP1):​c.913A>G​(p.Ile305Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00761 in 1,612,244 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (80 hom.)
• Consequence: RAB3GAP1 NM_012233.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0480

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005227387).
• BP6: Variant 2-135126596-A-G is Benign according to our data. Variant chr2-135126596-A-G is described in ClinVar as [Benign]. Clinvar id is 130072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-135126596-A-G is described in Lovd as [Likely_benign]. Variant chr2-135126596-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00655 (998/152310) while in subpopulation SAS AF= 0.0228 (110/4820). AF 95% confidence interval is 0.0194. There are 4 homozygotes in gnomad4. There are 463 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB3GAP1	NM_012233.3	c.913A>G	p.Ile305Val	missense_variant	11/24	ENST00000264158.13	NP_036365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB3GAP1	ENST00000264158.13	c.913A>G	p.Ile305Val	missense_variant	11/24	1	NM_012233.3	ENSP00000264158	A1

Frequencies

GnomAD3 genomes AF: 0.00657 AC: 1000 AN: 152192 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00860

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00874 AC: 2198 AN: 251426 Hom.: 20 AF XY: 0.00985 AC XY: 1339 AN XY: 135886

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00512

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0196

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00928

Gnomad OTH exome AF: 0.00961

GnomAD4 exome AF: 0.00773 AC: 11279 AN: 1459934 Hom.: 80 Cov.: 30 AF XY: 0.00830 AC XY: 6031 AN XY: 726446

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00521

Gnomad4 ASJ exome AF: 0.0198

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0187

Gnomad4 FIN exome AF: 0.00243

Gnomad4 NFE exome AF: 0.00735

Gnomad4 OTH exome AF: 0.00827

GnomAD4 genome AF: 0.00655 AC: 998 AN: 152310 Hom.: 4 Cov.: 32 AF XY: 0.00621 AC XY: 463 AN XY: 74498

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.00784

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.00860

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00959 Hom.: 16

Bravo AF: 0.00631

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0100 AC: 86

ExAC AF: 0.00893 AC: 1084

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0118

EpiControl AF: 0.0122

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 29, 2020	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

RAB3GAP1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2019

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.8
DANN	Benign	0.68
DEOGEN2	Benign	0.061	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.78	T;T;T
MetaRNN	Benign	0.0052	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.27	N;N;N
REVEL	Benign	0.097
Sift	Benign	0.34	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.13
MVP		0.18
MPC		0.18
ClinPred		0.0016	T
GERP RS		-5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.028
gMVP		0.29

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

Other links and lift over

dbSNP: rs116775947; hg19: chr2-135884166;