2-135150276-T-C

Variant names:

• chr2-135150276-T-C
• rs3739028
• NM_012233.3:c.1924-93T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.104
• Publications: 3 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]

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

Our verdict: Benign. The variant received -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
RAB3GAP1	NM_012233.3	c.1924-93T>C		intron_variant	Intron 17 of 23	ENST00000264158.13	NP_036365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB3GAP1	ENST00000264158.13	c.1924-93T>C		intron_variant	Intron 17 of 23	1	NM_012233.3	ENSP00000264158.8

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

African (AFR) AF: 0.0454 AC: 1374 AN: 30232

American (AMR) AF: 0.0867 AC: 3703 AN: 42734

Ashkenazi Jewish (ASJ) AF: 0.0290 AC: 728 AN: 25090

East Asian (EAS) AF: 0.154 AC: 5975 AN: 38742

South Asian (SAS) AF: 0.133 AC: 10836 AN: 81390

European-Finnish (FIN) AF: 0.0116 AC: 611 AN: 52686

Middle Eastern (MID) AF: 0.0433 AC: 229 AN: 5290

European-Non Finnish (NFE) AF: 0.0131 AC: 12864 AN: 985184

Other (OTH) AF: 0.0390 AC: 2162 AN: 55394

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

African (AFR) AF: 0.0427 AC: 1774 AN: 41578

American (AMR) AF: 0.0837 AC: 1280 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3470

East Asian (EAS) AF: 0.182 AC: 945 AN: 5186

South Asian (SAS) AF: 0.158 AC: 762 AN: 4820

European-Finnish (FIN) AF: 0.0120 AC: 127 AN: 10618

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0151 AC: 1029 AN: 68038

Other (OTH) AF: 0.0460 AC: 97 AN: 2110

Alfa AF: 0.0254 Hom.: 131

Bravo AF: 0.0423

Asia WGS AF: 0.165 AC: 574 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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