2-135150276-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_012233.3(RAB3GAP1):c.1924-93T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0304 in 1,469,062 control chromosomes in the GnomAD database, including 2,042 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.040 (282 hom., cov: 32)
  • Exomes 𝑓: 0.029 (1760 hom.)
• Consequence: RAB3GAP1 NM_012233.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.104

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 2-135150276-T-C is Benign according to our data. Variant chr2-135150276-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 668610.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB3GAP1	NM_012233.3	c.1924-93T>C		intron_variant		ENST00000264158.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB3GAP1	ENST00000264158.13	c.1924-93T>C		intron_variant		1	NM_012233.3	A1

Frequencies

GnomAD3 genomes AF: 0.0404 AC: 6153 AN: 152202 Hom.: 284 Cov.: 32

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0841

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0441

GnomAD4 exome AF: 0.0292 AC: 38482 AN: 1316742 Hom.: 1760 AF XY: 0.0321 AC XY: 21256 AN XY: 661908

Gnomad4 AFR exome AF: 0.0454

Gnomad4 AMR exome AF: 0.0867

Gnomad4 ASJ exome AF: 0.0290

Gnomad4 EAS exome AF: 0.154

Gnomad4 SAS exome AF: 0.133

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.0390

GnomAD4 genome AF: 0.0404 AC: 6149 AN: 152320 Hom.: 282 Cov.: 32 AF XY: 0.0439 AC XY: 3273 AN XY: 74486

Gnomad4 AFR AF: 0.0427

Gnomad4 AMR AF: 0.0837

Gnomad4 ASJ AF: 0.0285

Gnomad4 EAS AF: 0.182

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.0120

Gnomad4 NFE AF: 0.0151

Gnomad4 OTH AF: 0.0460

Alfa AF: 0.0256 Hom.: 81

Bravo AF: 0.0423

Asia WGS AF: 0.165 AC: 574 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	7.1
Dann	Benign	0.49

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: rs3739028; hg19: chr2-135907846; COSMIC: COSV51482556;