rs76927619

Positions:

• chr2-135120839-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012233.3(RAB3GAP1):​c.669G>T​(p.Leu223Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0013 in 1,611,940 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L223L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0070 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00070 (12 hom.)
• Consequence: RAB3GAP1 NM_012233.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.16

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0094305575).
• BP6: Variant 2-135120839-G-T is Benign according to our data. Variant chr2-135120839-G-T is described in ClinVar as [Benign]. Clinvar id is 130071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-135120839-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00704 (1072/152236) while in subpopulation AFR AF= 0.0241 (1001/41558). AF 95% confidence interval is 0.0228. There are 12 homozygotes in gnomad4. There are 531 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB3GAP1	NM_012233.3	c.669G>T	p.Leu223Phe	missense_variant	8/24	ENST00000264158.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB3GAP1	ENST00000264158.13	c.669G>T	p.Leu223Phe	missense_variant	8/24	1	NM_012233.3	A1

Frequencies

GnomAD3 genomes AF: 0.00699 AC: 1064 AN: 152118 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00175 AC: 441 AN: 251414 Hom.: 7 AF XY: 0.00128 AC XY: 174 AN XY: 135878

Gnomad AFR exome AF: 0.0241

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000704 AC: 1028 AN: 1459704 Hom.: 12 Cov.: 31 AF XY: 0.000607 AC XY: 441 AN XY: 726322

Gnomad4 AFR exome AF: 0.0253

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00704 AC: 1072 AN: 152236 Hom.: 12 Cov.: 33 AF XY: 0.00713 AC XY: 531 AN XY: 74430

Gnomad4 AFR AF: 0.0241

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00108 Hom.: 2

Bravo AF: 0.00773

ESP6500AA AF: 0.0213 AC: 94

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00215 AC: 261

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	RAB3GAP1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 14, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 26, 2016	- -

Warburg micro syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	T;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D
MetaRNN	Benign	0.0094	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.2	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.058	T;T;T
Polyphen		0.99	D;.;.
Vest4		0.60
MutPred		0.47		Loss of catalytic residue at L223 (P = 0.0308);Loss of catalytic residue at L223 (P = 0.0308);.;
MVP		0.76
MPC		0.28
ClinPred		0.029	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs76927619; hg19: chr2-135878409;