2-135052312-C-T

Position:

• chr2-135052312-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012233.3(RAB3GAP1):​c.5C>T​(p.Ala2Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000089 in 1,461,464 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: RAB3GAP1 NM_012233.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.48

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB3GAP1	NM_012233.3	c.5C>T	p.Ala2Val	missense_variant	1/24	ENST00000264158.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB3GAP1	ENST00000264158.13	c.5C>T	p.Ala2Val	missense_variant	1/24	1	NM_012233.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461464 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 727000

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2023

The c.5C>T (p.A2V) alteration is located in exon 1 (coding exon 1) of the RAB3GAP1 gene. This alteration results from a C to T substitution at nucleotide position 5, causing the alanine (A) at amino acid position 2 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.0083	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.052	T;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.61	D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	2.0	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.48	N;N;N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.070	T;T;D
Polyphen		0.99	D;.;.
Vest4		0.60
MutPred		0.30		Loss of glycosylation at S5 (P = 0.1204);Loss of glycosylation at S5 (P = 0.1204);Loss of glycosylation at S5 (P = 0.1204);
MVP		0.68
MPC		0.83
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.57
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs1054926336; hg19: chr2-135809882;