chr2-135120919-G-A

Variant names:

• chr2-135120919-G-A
• rs587776651
• NM_012233.3:c.748+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_012233.3(RAB3GAP1):​c.748+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,415,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RAB3GAP1 NM_012233.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 9.86
• Publications: 4 publications found

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: Labcorp Genetics (formerly Invitae), G2P
• cataract-intellectual disability-hypogonadism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-135120919-G-A is Pathogenic according to our data. Variant chr2-135120919-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB3GAP1	NM_012233.3	MANE Select	c.748+1G>A		splice_donor intron	N/A	NP_036365.1
	RAB3GAP1	NM_001172435.2		c.748+1G>A		splice_donor intron	N/A	NP_001165906.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB3GAP1	ENST00000264158.13	TSL:1 MANE Select	c.748+1G>A		splice_donor intron	N/A	ENSP00000264158.8
	RAB3GAP1	ENST00000442034.5	TSL:1	c.748+1G>A		splice_donor intron	N/A	ENSP00000411418.1
	RAB3GAP1	ENST00000688182.1		c.151-46774G>A		intron	N/A	ENSP00000509324.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1415014 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 706422

African (AFR) AF: 0.00 AC: 0 AN: 32340

American (AMR) AF: 0.00 AC: 0 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25878

East Asian (EAS) AF: 0.00 AC: 0 AN: 39438

South Asian (SAS) AF: 0.00 AC: 0 AN: 85250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 9.35e-7 AC: 1 AN: 1069612

Other (OTH) AF: 0.00 AC: 0 AN: 58780

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 28, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.748+1G>A variant in the RAB3GAP1 gene has been reported previously in association with Warburg Micro syndrome, and is considered a founder mutation in the Turkish population (Handley et al., 2013). This splice site variant destroys the canonical splice donor site of intron 8. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.748+1G>A variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.748+1G>A as a pathogenic variant.

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 8 of the RAB3GAP1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RAB3GAP1 are known to be pathogenic (PMID: 23420520). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Warburg Micro syndrome (PMID: 15696165, 23420520, 26852512). ClinVar contains an entry for this variant (Variation ID: 7058). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RAB3GAP1: PVS1, PM2, PM3

Warburg micro syndrome 1 Pathogenic:3 Other:1

May 02, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The homozygous c.748+1G>A variant in RAB3GAP1 was identified by our study in one individual with congenital cataracts, corpus callosum atrophy, spastic tetraparesis, and neurodevelopmental delay. The c.748+1G>A variant in RAB3GAP1 has been previously reported in 10 individuals with Warburg micro syndrome 1 (PMID: 31319225, PMID: 23420520, PMID: 26852512, PMID: 17351351, PMID: 15696165), but has been identified in 0.0008% (1/125568) of chromosomes by TopMed Bravo (https://bravo.sph.umich.edu/, dbSNP ID: rs587776651). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 7058) and has been interpreted as pathogenic by GeneDx, Erasmus Medical Center, Invitae, Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, and OMIM. The 10 affected individuals previously reported were homozygotes (PMID: 31319225, PMID: 23420520, PMID: 26852512, PMID: 17351351, PMID: 15696165), which increases the likelihood that the c.748+1G>A variant is pathogenic. This variant is located in the 5’ splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. Loss of function of the RAB3GAP1 gene is an established disease mechanism in autosomal recessive Warburg micro syndrome 1. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Warburg micro syndrome 1. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3 (Richards 2015).

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

May 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Sep 22, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Pathogenic:1

Jun 17, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.748+1G>A intronic variant results from a G to A substitution one nucleotide(s) after coding exon 8 of the RAB3GAP1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation has been reported in the homozygous state is several Turkish individuals with Warburg micro syndrome (Aligianis, 2005; Morris-Rosendahl, 2010; Handley, 2012; Handley, 2013; Tasdemir, 2015). Based on the available evidence, this alteration is classified as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.9
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587776651; hg19: chr2-135878489;