2-135162824-C-T

Position:

• chr2-135162824-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_012233.3(RAB3GAP1):​c.2463C>T​(p.Phe821Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00812 in 1,612,868 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (96 hom.)
• Consequence: RAB3GAP1 NM_012233.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.359

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:):

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 2-135162824-C-T is Benign according to our data. Variant chr2-135162824-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 130068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-135162824-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.359 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00814 (1239/152286) while in subpopulation NFE AF= 0.0105 (715/68032). AF 95% confidence interval is 0.00987. There are 14 homozygotes in gnomad4. There are 631 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB3GAP1	NM_012233.3	c.2463C>T	p.Phe821Phe	synonymous_variant	21/24	ENST00000264158.13	NP_036365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB3GAP1	ENST00000264158.13	c.2463C>T	p.Phe821Phe	synonymous_variant	21/24	1	NM_012233.3	ENSP00000264158.8

Frequencies

GnomAD3 genomes AF: 0.00814 AC: 1239 AN: 152168 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.0403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00937 AC: 2350 AN: 250708 Hom.: 28 AF XY: 0.00984 AC XY: 1336 AN XY: 135716

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.00813

Gnomad ASJ exome AF: 0.0413

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00203

Gnomad FIN exome AF: 0.00989

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0123

GnomAD4 exome AF: 0.00811 AC: 11850 AN: 1460582 Hom.: 96 Cov.: 30 AF XY: 0.00821 AC XY: 5965 AN XY: 726696

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00881

Gnomad4 ASJ exome AF: 0.0403

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00212

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.00809

Gnomad4 OTH exome AF: 0.00951

GnomAD4 genome AF: 0.00814 AC: 1239 AN: 152286 Hom.: 14 Cov.: 33 AF XY: 0.00847 AC XY: 631 AN XY: 74466

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.00981

Gnomad4 ASJ AF: 0.0403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.0113

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.0112 Hom.: 6

Bravo AF: 0.00800

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0164

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2015	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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	RAB3GAP1: BP4, BP7, BS2 -
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

Apr 16, 2024

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

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	7.0
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61748693; hg19: chr2-135920394;