rs7595725

Variant names:

• chr2-135150437-G-A
• rs7595725
• NM_012233.3:c.1992G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012233.3(RAB3GAP1):​c.1992G>A​(p.Ser664Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00546 in 1,614,136 control chromosomes in the GnomAD database, including 352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (166 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (186 hom.)
• Consequence: RAB3GAP1 NM_012233.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.68
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-135150437-G-A is Benign according to our data. Variant chr2-135150437-G-A is described in ClinVar as Benign. ClinVar VariationId is 130065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.68 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0901 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB3GAP1	NM_012233.3	MANE Select	c.1992G>A	p.Ser664Ser	synonymous	Exon 18 of 24	NP_036365.1	B9A6J2
	RAB3GAP1	NM_001172435.2		c.1992G>A	p.Ser664Ser	synonymous	Exon 18 of 25	NP_001165906.1	Q15042-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB3GAP1	ENST00000264158.13	TSL:1 MANE Select	c.1992G>A	p.Ser664Ser	synonymous	Exon 18 of 24	ENSP00000264158.8	Q15042-1
	RAB3GAP1	ENST00000442034.5	TSL:1	c.1992G>A	p.Ser664Ser	synonymous	Exon 18 of 25	ENSP00000411418.1	Q15042-3
	ZRANB3	ENST00000412849.5	TSL:1	n.2140+2424C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0270 AC: 4103 AN: 152134 Hom.: 162 Cov.: 32

Gnomad AFR AF: 0.0923

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.00745 AC: 1873 AN: 251454 AF XY: 0.00549

Gnomad AFR exome AF: 0.0951

Gnomad AMR exome AF: 0.00538

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000554

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00321 AC: 4687 AN: 1461884 Hom.: 186 Cov.: 31 AF XY: 0.00281 AC XY: 2044 AN XY: 727244

African (AFR) AF: 0.0998 AC: 3340 AN: 33478

American (AMR) AF: 0.00657 AC: 294 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00398 AC: 104 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00920 AC: 53 AN: 5764

European-Non Finnish (NFE) AF: 0.000382 AC: 425 AN: 1112008

Other (OTH) AF: 0.00745 AC: 450 AN: 60396

GnomAD4 genome AF: 0.0271 AC: 4126 AN: 152252 Hom.: 166 Cov.: 32 AF XY: 0.0271 AC XY: 2020 AN XY: 74460

African (AFR) AF: 0.0926 AC: 3844 AN: 41516

American (AMR) AF: 0.0115 AC: 176 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000617 AC: 42 AN: 68032

Other (OTH) AF: 0.0204 AC: 43 AN: 2108

Alfa AF: 0.0102 Hom.: 97

Bravo AF: 0.0310

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	RAB3GAP1-related disorder (1)
-	-	1	Warburg micro syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.2
DANN	Benign	0.81
PhyloP100		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs7595725; hg19: chr2-135908007;