rs4954222

Positions:

• chr2-135154685-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB3GAP1	NM_012233.3	c.2289+809A>G		intron_variant		ENST00000264158.13	NP_036365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB3GAP1	ENST00000264158.13	c.2289+809A>G		intron_variant		1	NM_012233.3	ENSP00000264158	A1

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

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.246

Gnomad4 SAS AF: 0.319

Gnomad4 FIN AF: 0.0629

Gnomad4 NFE AF: 0.0801

Gnomad4 OTH AF: 0.144

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.2
DANN	Benign	0.78

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: rs4954222; hg19: chr2-135912255;