2-135135802-A-G

Variant names:

• chr2-135135802-A-G
• rs10445686
• NM_012233.3:c.1793A>G

Variant summary

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

The NM_012233.3(RAB3GAP1):​c.1793A>G​(p.Asn598Ser) variant causes a missense change. The variant allele was found at a frequency of 0.147 in 1,613,824 control chromosomes in the GnomAD database, including 24,629 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2387 hom., cov: 32)
  • Exomes 𝑓: 0.15 (22242 hom.)
• Consequence: RAB3GAP1 NM_012233.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.03
• Publications: 43 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: G2P, Labcorp Genetics (formerly Invitae)
• 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 (MetaRNN=0.003854096).
• BP6: Variant 2-135135802-A-G is Benign according to our data. Variant chr2-135135802-A-G is described in ClinVar as Benign. ClinVar VariationId is 130064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 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.1793A>G	p.Asn598Ser	missense	Exon 17 of 24	NP_036365.1	B9A6J2
	RAB3GAP1	NM_001172435.2		c.1793A>G	p.Asn598Ser	missense	Exon 17 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.1793A>G	p.Asn598Ser	missense	Exon 17 of 24	ENSP00000264158.8	Q15042-1
	RAB3GAP1	ENST00000442034.5	TSL:1	c.1793A>G	p.Asn598Ser	missense	Exon 17 of 25	ENSP00000411418.1	Q15042-3
	RAB3GAP1	ENST00000970735.1		c.1796A>G	p.Asn599Ser	missense	Exon 17 of 24	ENSP00000640794.1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22013 AN: 152076 Hom.: 2384 Cov.: 32

Gnomad AFR AF: 0.0371

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.204

GnomAD2 exomes AF: 0.204 AC: 51342 AN: 251228 AF XY: 0.211

Gnomad AFR exome AF: 0.0327

Gnomad AMR exome AF: 0.249

Gnomad ASJ exome AF: 0.397

Gnomad EAS exome AF: 0.389

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.154

Gnomad OTH exome AF: 0.237

GnomAD4 exome AF: 0.147 AC: 214878 AN: 1461630 Hom.: 22242 Cov.: 33 AF XY: 0.154 AC XY: 112059 AN XY: 727132

African (AFR) AF: 0.0359 AC: 1202 AN: 33474

American (AMR) AF: 0.244 AC: 10892 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 10238 AN: 26132

East Asian (EAS) AF: 0.404 AC: 16023 AN: 39696

South Asian (SAS) AF: 0.287 AC: 24760 AN: 86252

European-Finnish (FIN) AF: 0.148 AC: 7879 AN: 53414

Middle Eastern (MID) AF: 0.345 AC: 1990 AN: 5766

European-Non Finnish (NFE) AF: 0.118 AC: 130815 AN: 1111798

Other (OTH) AF: 0.183 AC: 11079 AN: 60384

GnomAD4 genome AF: 0.145 AC: 22033 AN: 152194 Hom.: 2387 Cov.: 32 AF XY: 0.151 AC XY: 11252 AN XY: 74392

African (AFR) AF: 0.0370 AC: 1539 AN: 41558

American (AMR) AF: 0.229 AC: 3506 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1388 AN: 3468

East Asian (EAS) AF: 0.383 AC: 1975 AN: 5160

South Asian (SAS) AF: 0.294 AC: 1421 AN: 4826

European-Finnish (FIN) AF: 0.144 AC: 1526 AN: 10590

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 10004 AN: 67990

Other (OTH) AF: 0.209 AC: 442 AN: 2114

Alfa AF: 0.166 Hom.: 8451

Bravo AF: 0.144

TwinsUK AF: 0.108 AC: 399

ALSPAC AF: 0.111 AC: 427

ESP6500AA AF: 0.0313 AC: 138

ESP6500EA AF: 0.154 AC: 1324

ExAC AF: 0.201 AC: 24339

Asia WGS AF: 0.321 AC: 1117 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.066
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.92	L
PhyloP100		5.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.14
Sift	Benign	0.26	T
Sift4G	Benign	0.82	T
Polyphen		0.0010	B
Vest4		0.073
MPC		0.18
ClinPred		0.010	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.084
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: rs10445686; hg19: chr2-135893372; COSMIC: COSV51482881; COSMIC: COSV51482881;