rs56786863

chr2-135162538-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012233.3(RAB3GAP1):c.2290-17C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0265 in 1,590,360 control chromosomes in the GnomAD database, including 1,430 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (528 hom., cov: 32)
  • Exomes 𝑓: 0.023 (902 hom.)
• Consequence: RAB3GAP1 NM_012233.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.67

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-135162538-C-T is Benign according to our data. Variant chr2-135162538-C-T is described in ClinVar as [Benign]. Clinvar id is 138860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-135162538-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB3GAP1	NM_012233.3	c.2290-17C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000264158.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB3GAP1	ENST00000264158.13	c.2290-17C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_012233.3	A1

Frequencies

GnomAD3 genomes AF: 0.0606 AC: 9212 AN: 152008 Hom.: 528 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0421

Gnomad ASJ AF: 0.0599

Gnomad EAS AF: 0.0569

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0535

GnomAD3 exomes AF: 0.0346 AC: 8535 AN: 246450 Hom.: 312 AF XY: 0.0311 AC XY: 4133 AN XY: 133098

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.0399

Gnomad ASJ exome AF: 0.0661

Gnomad EAS exome AF: 0.0490

Gnomad SAS exome AF: 0.0121

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.0207

Gnomad OTH exome AF: 0.0307

GnomAD4 exome AF: 0.0229 AC: 32889 AN: 1438234 Hom.: 902 Cov.: 28 AF XY: 0.0229 AC XY: 16397 AN XY: 716454

Gnomad4 AFR exome AF: 0.155

Gnomad4 AMR exome AF: 0.0389

Gnomad4 ASJ exome AF: 0.0702

Gnomad4 EAS exome AF: 0.0536

Gnomad4 SAS exome AF: 0.0120

Gnomad4 FIN exome AF: 0.0176

Gnomad4 NFE exome AF: 0.0166

Gnomad4 OTH exome AF: 0.0317

GnomAD4 genome AF: 0.0607 AC: 9229 AN: 152126 Hom.: 528 Cov.: 32 AF XY: 0.0587 AC XY: 4367 AN XY: 74376

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.0422

Gnomad4 ASJ AF: 0.0599

Gnomad4 EAS AF: 0.0570

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.0140

Gnomad4 NFE AF: 0.0211

Gnomad4 OTH AF: 0.0539

Alfa AF: 0.0501 Hom.: 62

Bravo AF: 0.0669

Asia WGS AF: 0.0330 AC: 116 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2014	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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 15, 2015	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.18
Dann	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs56786863; hg19: chr2-135920108;