chr2-135133038-G-C

Variant names:

• chr2-135133038-G-C
• rs2305594
• NM_012233.3:c.1326+54G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000264158.13(RAB3GAP1):​c.1326+54G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,068,816 control chromosomes in the GnomAD database, including 9,447 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1294 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8153 hom.)
• Consequence: RAB3GAP1 ENST00000264158.13 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.446
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-135133038-G-C is Benign according to our data. Variant chr2-135133038-G-C is described in ClinVar as Benign. ClinVar VariationId is 1222267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000264158.13. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB3GAP1	NM_012233.3	MANE Select	c.1326+54G>C		intron	N/A	NP_036365.1
	RAB3GAP1	NM_001172435.2		c.1326+54G>C		intron	N/A	NP_001165906.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB3GAP1	ENST00000264158.13	TSL:1 MANE Select	c.1326+54G>C		intron	N/A	ENSP00000264158.8
	RAB3GAP1	ENST00000442034.5	TSL:1	c.1326+54G>C		intron	N/A	ENSP00000411418.1
	RAB3GAP1	ENST00000688182.1		c.151-34655G>C		intron	N/A	ENSP00000509324.1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17408 AN: 151984 Hom.: 1299 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.0630

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.0794

Gnomad OTH AF: 0.142

GnomAD4 exome AF: 0.107 AC: 98432 AN: 916714 Hom.: 8153 AF XY: 0.115 AC XY: 54942 AN XY: 478746

African (AFR) AF: 0.116 AC: 2635 AN: 22806

American (AMR) AF: 0.212 AC: 9214 AN: 43402

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 2865 AN: 22570

East Asian (EAS) AF: 0.230 AC: 8497 AN: 36932

South Asian (SAS) AF: 0.282 AC: 20970 AN: 74378

European-Finnish (FIN) AF: 0.0598 AC: 3019 AN: 50524

Middle Eastern (MID) AF: 0.189 AC: 661 AN: 3502

European-Non Finnish (NFE) AF: 0.0737 AC: 45719 AN: 620366

Other (OTH) AF: 0.115 AC: 4852 AN: 42234

GnomAD4 genome AF: 0.114 AC: 17415 AN: 152102 Hom.: 1294 Cov.: 32 AF XY: 0.119 AC XY: 8867 AN XY: 74358

African (AFR) AF: 0.111 AC: 4607 AN: 41514

American (AMR) AF: 0.200 AC: 3053 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 452 AN: 3468

East Asian (EAS) AF: 0.247 AC: 1277 AN: 5172

South Asian (SAS) AF: 0.317 AC: 1531 AN: 4824

European-Finnish (FIN) AF: 0.0630 AC: 667 AN: 10584

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.0794 AC: 5395 AN: 67950

Other (OTH) AF: 0.144 AC: 302 AN: 2104

Alfa AF: 0.0940 Hom.: 102

Bravo AF: 0.121

Asia WGS AF: 0.286 AC: 990 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.56
PhyloP100		-0.45
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: rs2305594; hg19: chr2-135890608;