rs12045447

Variant names:

• chr1-220171111-T-C
• rs12045447
• NM_012414.4:c.2587A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:10
• Conservation: PhyloP100: 0.601
• Publications: 19 publications found

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]

RAB3GAP2 Gene-Disease associations (from GenCC):

• Martsolf syndrome 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• RAB18 deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• Warburg micro syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Warburg micro syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal recessive spastic paraplegia type 69

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• 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=0.0012030005).
• BP6: Variant 1-220171111-T-C is Benign according to our data. Variant chr1-220171111-T-C is described in ClinVar as Benign. ClinVar VariationId is 130078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012414.4. 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
	RAB3GAP2	NM_012414.4	MANE Select	c.2587A>G	p.Thr863Ala	missense	Exon 24 of 35	NP_036546.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB3GAP2	ENST00000358951.7	TSL:1 MANE Select	c.2587A>G	p.Thr863Ala	missense	Exon 24 of 35	ENSP00000351832.2	Q9H2M9-1
	RAB3GAP2	ENST00000692972.1		c.2662A>G	p.Thr888Ala	missense	Exon 25 of 36	ENSP00000510753.1	A0A8I5KZB3
	RAB3GAP2	ENST00000691661.1		c.2599A>G	p.Thr867Ala	missense	Exon 24 of 35	ENSP00000510185.1	A0A8I5KYQ0

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

GnomAD2 exomes AF: 0.0384 AC: 9634 AN: 250970 AF XY: 0.0386

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 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

African (AFR) AF: 0.0842 AC: 2817 AN: 33460

American (AMR) AF: 0.0277 AC: 1237 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0772 AC: 2017 AN: 26124

East Asian (EAS) AF: 0.0359 AC: 1425 AN: 39696

South Asian (SAS) AF: 0.0380 AC: 3281 AN: 86246

European-Finnish (FIN) AF: 0.00959 AC: 512 AN: 53416

Middle Eastern (MID) AF: 0.0679 AC: 391 AN: 5760

European-Non Finnish (NFE) AF: 0.0338 AC: 37518 AN: 1111644

Other (OTH) AF: 0.0457 AC: 2757 AN: 60374

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

African (AFR) AF: 0.0797 AC: 3307 AN: 41518

American (AMR) AF: 0.0360 AC: 550 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0890 AC: 309 AN: 3470

East Asian (EAS) AF: 0.0361 AC: 187 AN: 5174

South Asian (SAS) AF: 0.0429 AC: 207 AN: 4820

European-Finnish (FIN) AF: 0.00791 AC: 84 AN: 10614

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0353 AC: 2401 AN: 68008

Other (OTH) AF: 0.0529 AC: 112 AN: 2116

Alfa AF: 0.0407 Hom.: 542

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Martsolf syndrome (2)
-	-	2	Warburg micro syndrome 2 (2)
-	-	1	Martsolf syndrome;C3280214:Warburg micro syndrome 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.60
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12045447; hg19: chr1-220344453;