rs4954221

Variant names:

• chr2-135151892-G-A
• rs4954221
• NM_012233.3:c.2061+1386G>A

Variant summary

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

The NM_012233.3(RAB3GAP1):​c.2061+1386G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 152,106 control chromosomes in the GnomAD database, including 11,370 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 0.31 (11370 hom., cov: 32)
• Consequence: RAB3GAP1 NM_012233.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0150
• Publications: 18 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB3GAP1	NM_012233.3	c.2061+1386G>A		intron_variant	Intron 18 of 23	ENST00000264158.13	NP_036365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB3GAP1	ENST00000264158.13	c.2061+1386G>A		intron_variant	Intron 18 of 23	1	NM_012233.3	ENSP00000264158.8

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47506 AN: 151988 Hom.: 11323 Cov.: 32

Gnomad AFR AF: 0.653

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.297

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

GnomAD4 genome AF: 0.313 AC: 47609 AN: 152106 Hom.: 11370 Cov.: 32 AF XY: 0.315 AC XY: 23418 AN XY: 74376

African (AFR) AF: 0.654 AC: 27103 AN: 41448

American (AMR) AF: 0.325 AC: 4964 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 858 AN: 3470

East Asian (EAS) AF: 0.305 AC: 1580 AN: 5172

South Asian (SAS) AF: 0.384 AC: 1855 AN: 4826

European-Finnish (FIN) AF: 0.137 AC: 1455 AN: 10590

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9021 AN: 67996

Other (OTH) AF: 0.298 AC: 628 AN: 2106

Alfa AF: 0.176 Hom.: 2952

Bravo AF: 0.338

Asia WGS AF: 0.373 AC: 1296 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.46
PhyloP100		0.015
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: rs4954221; hg19: chr2-135909462;