rs4954222

Variant names:

• chr2-135154685-A-G
• rs4954222
• NM_012233.3:c.2289+809A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012233.3(RAB3GAP1):​c.2289+809A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 152,130 control chromosomes in the GnomAD database, including 1,289 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1289 hom., cov: 32)
• Consequence: RAB3GAP1 NM_012233.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.764
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012233.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB3GAP1	NM_012233.3	MANE Select	c.2289+809A>G		intron	N/A	NP_036365.1
	RAB3GAP1	NM_001172435.2		c.2289+809A>G		intron	N/A	NP_001165906.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB3GAP1	ENST00000264158.13	TSL:1 MANE Select	c.2289+809A>G		intron	N/A	ENSP00000264158.8
	RAB3GAP1	ENST00000442034.5	TSL:1	c.2289+809A>G		intron	N/A	ENSP00000411418.1
	ZRANB3	ENST00000412849.5	TSL:1	n.2007-1691T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17464 AN: 152012 Hom.: 1294 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.0791

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.0629

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.0801

Gnomad OTH AF: 0.143

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.115 AC: 17471 AN: 152130 Hom.: 1289 Cov.: 32 AF XY: 0.120 AC XY: 8892 AN XY: 74390

African (AFR) AF: 0.111 AC: 4608 AN: 41512

American (AMR) AF: 0.200 AC: 3059 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 453 AN: 3470

East Asian (EAS) AF: 0.246 AC: 1272 AN: 5174

South Asian (SAS) AF: 0.319 AC: 1530 AN: 4802

European-Finnish (FIN) AF: 0.0629 AC: 667 AN: 10612

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.0801 AC: 5447 AN: 67972

Other (OTH) AF: 0.144 AC: 305 AN: 2112

Alfa AF: 0.0947 Hom.: 102

Bravo AF: 0.121

Asia WGS AF: 0.288 AC: 998 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.2
DANN	Benign	0.78
PhyloP100		-0.76
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: rs4954222; hg19: chr2-135912255;