2-135153852-T-C

Variant names:

• chr2-135153852-T-C
• rs17261772
• NM_012233.3:c.2265T>C

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.2265T>C​(p.Phe755Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 1,613,426 control chromosomes in the GnomAD database, including 150,350 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (28389 hom., cov: 32)
  • Exomes 𝑓: 0.34 (121961 hom.)
• Consequence: RAB3GAP1 NM_012233.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.154
• Publications: 36 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=-0.52).
• BP6: Variant 2-135153852-T-C is Benign according to our data. Variant chr2-135153852-T-C is described in ClinVar as Benign. ClinVar VariationId is 130067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.154 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 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.2265T>C	p.Phe755Phe	synonymous	Exon 19 of 24	NP_036365.1	B9A6J2
	RAB3GAP1	NM_001172435.2		c.2265T>C	p.Phe755Phe	synonymous	Exon 19 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.2265T>C	p.Phe755Phe	synonymous	Exon 19 of 24	ENSP00000264158.8	Q15042-1
	RAB3GAP1	ENST00000442034.5	TSL:1	c.2265T>C	p.Phe755Phe	synonymous	Exon 19 of 25	ENSP00000411418.1	Q15042-3
	ZRANB3	ENST00000412849.5	TSL:1	n.2007-858A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.543 AC: 82449 AN: 151978 Hom.: 28324 Cov.: 32

Gnomad AFR AF: 0.868

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.715

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.730

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.594

GnomAD2 exomes AF: 0.520 AC: 130582 AN: 250934 AF XY: 0.512

Gnomad AFR exome AF: 0.878

Gnomad AMR exome AF: 0.727

Gnomad ASJ exome AF: 0.717

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.313

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.512

GnomAD4 exome AF: 0.340 AC: 496730 AN: 1461330 Hom.: 121961 Cov.: 36 AF XY: 0.352 AC XY: 256117 AN XY: 726952

African (AFR) AF: 0.897 AC: 30008 AN: 33468

American (AMR) AF: 0.718 AC: 32071 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.717 AC: 18730 AN: 26126

East Asian (EAS) AF: 0.999 AC: 39635 AN: 39690

South Asian (SAS) AF: 0.678 AC: 58483 AN: 86244

European-Finnish (FIN) AF: 0.312 AC: 16669 AN: 53400

Middle Eastern (MID) AF: 0.686 AC: 3954 AN: 5766

European-Non Finnish (NFE) AF: 0.244 AC: 270976 AN: 1111562

Other (OTH) AF: 0.434 AC: 26204 AN: 60376

GnomAD4 genome AF: 0.543 AC: 82579 AN: 152096 Hom.: 28389 Cov.: 32 AF XY: 0.555 AC XY: 41289 AN XY: 74370

African (AFR) AF: 0.869 AC: 36063 AN: 41516

American (AMR) AF: 0.669 AC: 10221 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.715 AC: 2478 AN: 3468

East Asian (EAS) AF: 0.996 AC: 5165 AN: 5186

South Asian (SAS) AF: 0.729 AC: 3512 AN: 4816

European-Finnish (FIN) AF: 0.312 AC: 3300 AN: 10570

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.297 AC: 20174 AN: 67956

Other (OTH) AF: 0.598 AC: 1260 AN: 2106

Alfa AF: 0.422 Hom.: 30511

Bravo AF: 0.582

Asia WGS AF: 0.882 AC: 3063 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	3	Warburg micro syndrome 1 (3)
-	-	1	Martsolf syndrome 2 (1)
-	-	1	Warburg micro syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.0
DANN	Benign	0.78
PhyloP100		0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17261772; hg19: chr2-135911422; COSMIC: COSV108040193;