2-135153852-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012233.3(RAB3GAP1):c.2265T>C(p.Phe755=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 1,613,426 control chromosomes in the GnomAD database, including 150,350 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (28389 hom., cov: 32)
  • Exomes 𝑓: 0.34 (121961 hom.)
• Consequence: RAB3GAP1 NM_012233.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.154

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]

ZRANB3 (HGNC:25249): (zinc finger RANBP2-type containing 3) Enables ATP-dependent DNA/DNA annealing activity; K63-linked polyubiquitin modification-dependent protein binding activity; and endodeoxyribonuclease activity. Involved in several processes, including DNA metabolic process; DNA rewinding; and negative regulation of DNA recombination. Located in nuclear replication fork and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-135153852-T-C is Benign according to our data. Variant chr2-135153852-T-C is described in ClinVar as [Benign]. Clinvar id is 130067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-135153852-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.154 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB3GAP1	NM_012233.3	c.2265T>C	p.Phe755=	synonymous_variant	19/24	ENST00000264158.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB3GAP1	ENST00000264158.13	c.2265T>C	p.Phe755=	synonymous_variant	19/24	1	NM_012233.3	A1

Frequencies

GnomAD3 genomes AF: 0.543 AC: 82449 AN: 151978 Hom.: 28324 Cov.: 32

Gnomad AFR AF: 0.868

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.715

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.730

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.594

GnomAD3 exomes AF: 0.520 AC: 130582 AN: 250934 Hom.: 43378 AF XY: 0.512 AC XY: 69433 AN XY: 135624

Gnomad AFR exome AF: 0.878

Gnomad AMR exome AF: 0.727

Gnomad ASJ exome AF: 0.717

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.687

Gnomad FIN exome AF: 0.313

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.512

GnomAD4 exome AF: 0.340 AC: 496730 AN: 1461330 Hom.: 121961 Cov.: 36 AF XY: 0.352 AC XY: 256117 AN XY: 726952

Gnomad4 AFR exome AF: 0.897

Gnomad4 AMR exome AF: 0.718

Gnomad4 ASJ exome AF: 0.717

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.678

Gnomad4 FIN exome AF: 0.312

Gnomad4 NFE exome AF: 0.244

Gnomad4 OTH exome AF: 0.434

GnomAD4 genome AF: 0.543 AC: 82579 AN: 152096 Hom.: 28389 Cov.: 32 AF XY: 0.555 AC XY: 41289 AN XY: 74370

Gnomad4 AFR AF: 0.869

Gnomad4 AMR AF: 0.669

Gnomad4 ASJ AF: 0.715

Gnomad4 EAS AF: 0.996

Gnomad4 SAS AF: 0.729

Gnomad4 FIN AF: 0.312

Gnomad4 NFE AF: 0.297

Gnomad4 OTH AF: 0.598

Alfa AF: 0.396 Hom.: 15359

Bravo AF: 0.582

Asia WGS AF: 0.882 AC: 3063 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -

Warburg micro syndrome 1 Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Warburg micro syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Martsolf syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	5.0
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17261772; hg19: chr2-135911422;