rs12045447

chr1-220171111-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012414.4(RAB3GAP2):c.2587A>G(p.Thr863Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 1,613,656 control chromosomes in the GnomAD database, including 1,366 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (215 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1151 hom.)
• Consequence: RAB3GAP2 NM_012414.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.601

Genes affected

RAB3GAP2 (HGNC:17168): (RAB3 GTPase activating non-catalytic protein subunit 2) The protein encoded by this gene belongs to the RAB3 protein family, members of which are involved in regulated exocytosis of neurotransmitters and hormones. This protein forms the Rab3 GTPase-activating complex with RAB3GAP1, where it constitutes the regulatory subunit, whereas the latter functions as the catalytic subunit. This gene has the highest level of expression in the brain, consistent with it having a key role in neurodevelopment. Mutations in this gene are associated with Martsolf syndrome.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012030005).
• BP6: Variant 1-220171111-T-C is Benign according to our data. Variant chr1-220171111-T-C is described in ClinVar as [Benign]. Clinvar id is 130078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220171111-T-C is described in Lovd as [Benign]. Variant chr1-220171111-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB3GAP2	NM_012414.4	c.2587A>G	p.Thr863Ala	missense_variant	24/35	ENST00000358951.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB3GAP2	ENST00000358951.7	c.2587A>G	p.Thr863Ala	missense_variant	24/35	1	NM_012414.4	P2

Frequencies

GnomAD3 genomes AF: 0.0471 AC: 7159 AN: 152100 Hom.: 210 Cov.: 32

Gnomad AFR AF: 0.0793

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0360

Gnomad ASJ AF: 0.0890

Gnomad EAS AF: 0.0359

Gnomad SAS AF: 0.0433

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0353

Gnomad OTH AF: 0.0506

GnomAD3 exomes AF: 0.0384 AC: 9634 AN: 250970 Hom.: 265 AF XY: 0.0386 AC XY: 5245 AN XY: 135712

Gnomad AFR exome AF: 0.0778

Gnomad AMR exome AF: 0.0262

Gnomad ASJ exome AF: 0.0778

Gnomad EAS exome AF: 0.0411

Gnomad SAS exome AF: 0.0378

Gnomad FIN exome AF: 0.00859

Gnomad NFE exome AF: 0.0379

Gnomad OTH exome AF: 0.0478

GnomAD4 exome AF: 0.0356 AC: 51955 AN: 1461438 Hom.: 1151 Cov.: 31 AF XY: 0.0359 AC XY: 26120 AN XY: 727056

Gnomad4 AFR exome AF: 0.0842

Gnomad4 AMR exome AF: 0.0277

Gnomad4 ASJ exome AF: 0.0772

Gnomad4 EAS exome AF: 0.0359

Gnomad4 SAS exome AF: 0.0380

Gnomad4 FIN exome AF: 0.00959

Gnomad4 NFE exome AF: 0.0338

Gnomad4 OTH exome AF: 0.0457

GnomAD4 genome AF: 0.0472 AC: 7188 AN: 152218 Hom.: 215 Cov.: 32 AF XY: 0.0458 AC XY: 3408 AN XY: 74430

Gnomad4 AFR AF: 0.0797

Gnomad4 AMR AF: 0.0360

Gnomad4 ASJ AF: 0.0890

Gnomad4 EAS AF: 0.0361

Gnomad4 SAS AF: 0.0429

Gnomad4 FIN AF: 0.00791

Gnomad4 NFE AF: 0.0353

Gnomad4 OTH AF: 0.0529

Alfa AF: 0.0411 Hom.: 248

Bravo AF: 0.0497

TwinsUK AF: 0.0254 AC: 94

ALSPAC AF: 0.0374 AC: 144

ESP6500AA AF: 0.0749 AC: 330

ESP6500EA AF: 0.0380 AC: 327

ExAC AF: 0.0401 AC: 4872

Asia WGS AF: 0.0470 AC: 163 AN: 3478

EpiCase AF: 0.0419

EpiControl AF: 0.0437

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2014	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. -

Warburg micro syndrome 2 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Martsolf syndrome Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Martsolf syndrome;C3280214:Warburg micro syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	14
Dann	Benign	0.81
DEOGEN2	Benign	0.024	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.056
Sift	Benign	0.75	T
Sift4G	Benign	0.58	T
Polyphen		0.0020	B
Vest4		0.015
MPC		0.14
ClinPred		0.00098	T
GERP RS		0.66
Varity_R		0.034
gMVP		0.19

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: rs12045447; hg19: chr1-220344453;