chr2-135093688-A-G

Variant names:

• chr2-135093688-A-G
• rs73959261
• NM_012233.3:c.357A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001172435.2(RAB3GAP1):​c.357A>G​(p.Val119Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,608,324 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (30 hom.)
• Consequence: RAB3GAP1 NM_001172435.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.301
• 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]

RAB3GAP1 Gene-Disease associations (from GenCC):

• Warburg micro syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Warburg micro syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• cataract-intellectual disability-hypogonadism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-135093688-A-G is Benign according to our data. Variant chr2-135093688-A-G is described in ClinVar as Benign. ClinVar VariationId is 130070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.301 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00961 (1463/152298) while in subpopulation AFR AF = 0.0336 (1398/41562). AF 95% confidence interval is 0.0322. There are 24 homozygotes in GnomAd4. There are 673 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001172435.2. 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.357A>G	p.Val119Val	synonymous	Exon 5 of 24	NP_036365.1
	RAB3GAP1	NM_001172435.2		c.357A>G	p.Val119Val	synonymous	Exon 5 of 25	NP_001165906.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB3GAP1	ENST00000264158.13	TSL:1 MANE Select	c.357A>G	p.Val119Val	synonymous	Exon 5 of 24	ENSP00000264158.8
	RAB3GAP1	ENST00000442034.5	TSL:1	c.357A>G	p.Val119Val	synonymous	Exon 5 of 25	ENSP00000411418.1
	RAB3GAP1	ENST00000970735.1		c.360A>G	p.Val120Val	synonymous	Exon 5 of 24	ENSP00000640794.1

Frequencies

GnomAD3 genomes AF: 0.00956 AC: 1455 AN: 152180 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00235 AC: 591 AN: 251466 AF XY: 0.00175

Gnomad AFR exome AF: 0.0325

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00103 AC: 1497 AN: 1456026 Hom.: 30 Cov.: 29 AF XY: 0.000876 AC XY: 635 AN XY: 724740

African (AFR) AF: 0.0375 AC: 1248 AN: 33308

American (AMR) AF: 0.00166 AC: 74 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5760

European-Non Finnish (NFE) AF: 0.0000154 AC: 17 AN: 1106760

Other (OTH) AF: 0.00229 AC: 138 AN: 60218

GnomAD4 genome AF: 0.00961 AC: 1463 AN: 152298 Hom.: 24 Cov.: 32 AF XY: 0.00904 AC XY: 673 AN XY: 74472

African (AFR) AF: 0.0336 AC: 1398 AN: 41562

American (AMR) AF: 0.00307 AC: 47 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00408 Hom.: 7

Bravo AF: 0.0110

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.4
DANN	Benign	0.79
PhyloP100		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=99/1	polymorphism

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: rs73959261; hg19: chr2-135851258;