rs139337049

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_012414.4(RAB3GAP2):c.2290C>T(p.Leu764Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,613,938 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L764I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00097 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 3 hom. )

Consequence

RAB3GAP2
NM_012414.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3

Conservation

PhyloP100: 2.46

Publications

5 publications found

Variant links:

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

RAB3GAP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010350466).

BP6

Variant 1-220182277-G-A is Benign according to our data. Variant chr1-220182277-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235683.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000973 (148/152176) while in subpopulation NFE AF = 0.00154 (105/68004). AF 95% confidence interval is 0.0013. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

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.2290C>T	p.Leu764Phe	missense	Exon 21 of 35	NP_036546.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAB3GAP2	ENST00000358951.7	TSL:1 MANE Select	c.2290C>T	p.Leu764Phe	missense	Exon 21 of 35	ENSP00000351832.2	Q9H2M9-1
RAB3GAP2	ENST00000692972.1		c.2365C>T	p.Leu789Phe	missense	Exon 22 of 36	ENSP00000510753.1	A0A8I5KZB3
RAB3GAP2	ENST00000691661.1		c.2302C>T	p.Leu768Phe	missense	Exon 21 of 35	ENSP00000510185.1	A0A8I5KYQ0

Frequencies

GnomAD3 genomes

AF:

0.000973

AC:

148

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00154

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00103

AC:

260

AN:

251316

AF XY:

0.000994

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00167

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00163

AC:

2386

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

1116

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.000402

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00188

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.000452

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00191

AC:

2125

AN:

1111942

Other (OTH)

AF:

0.00230

AC:

139

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

157

313

470

626

783

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000973

AC:

148

AN:

152176

Hom.:

Cov.:

AF XY:

0.000820

AC XY:

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41530

American (AMR)

AF:

0.000785

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000945

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00154

AC:

105

AN:

68004

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00137

Hom.:

Bravo

AF:

0.00102

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00106

AC:

129

EpiCase

AF:

0.00174

EpiControl

AF:

0.00148

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Martsolf syndrome;C3280214:Warburg micro syndrome 2 (2)

Martsolf syndrome (1)

not specified (1)

RAB3GAP2-related disorder (1)

Warburg micro syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.034

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.84

M_CAP

Benign

0.0065

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.40

PhyloP100

2.5

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.4

REVEL

Benign

0.025

Sift

Benign

0.36

Sift4G

Benign

0.37

Polyphen

0.0010

Vest4

0.20

MVP

0.11

MPC

0.16

ClinPred

0.016

GERP RS

2.9

Varity_R

0.12

gMVP

0.44

Mutation Taster

=82/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over