rs575925720

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_012414.4(RAB3GAP2):c.812-6T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000241 in 452,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 21)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

RAB3GAP2
NM_012414.4 splice_region, intron

Scores

Splicing: ADA: 0.00006824

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.00300

Publications

0 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: ClinGen, Orphanet
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 -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 1-220196404-A-T is Benign according to our data. Variant chr1-220196404-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 463032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000266 (99/371810) while in subpopulation MID AF = 0.00092 (2/2174). AF 95% confidence interval is 0.000321. There are 0 homozygotes in GnomAdExome4. There are 52 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB3GAP2	NM_012414.4 link	c.812-6T>A		splice_region_variant, intron_variant	Intron 9 of 34	ENST00000358951.7	NP_036546.2	Q9H2M9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB3GAP2	ENST00000358951.7 link	c.812-6T>A		splice_region_variant, intron_variant	Intron 9 of 34	1	NM_012414.4	ENSP00000351832.2		Q9H2M9-1

Frequencies

GnomAD3 genomes

AF:

0.000124

AC:

AN:

80754

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000134

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000145

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000526

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000108

AC:

AN:

176608

AF XY:

0.0000740

show subpopulations

Gnomad AFR exome

AF:

0.0000836

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000695

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.000488

GnomAD4 exome

AF:

0.000266

AC:

AN:

371810

Hom.:

Cov.:

AF XY:

0.000279

AC XY:

AN XY:

186482

show subpopulations

African (AFR)

AF:

0.000353

AC:

AN:

8492

American (AMR)

AF:

0.000738

AC:

AN:

8132

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8168

East Asian (EAS)

AF:

0.000130

AC:

AN:

7670

South Asian (SAS)

AF:

0.000402

AC:

AN:

22366

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13326

Middle Eastern (MID)

AF:

0.000920

AC:

AN:

2174

European-Non Finnish (NFE)

AF:

0.000255

AC:

AN:

286276

Other (OTH)

AF:

0.000329

AC:

AN:

15206

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000124

AC:

AN:

80758

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

AN XY:

38908

show subpopulations

African (AFR)

AF:

0.000134

AC:

AN:

22442

American (AMR)

AF:

0.000145

AC:

AN:

6912

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2506

East Asian (EAS)

AF:

0.000527

AC:

AN:

1898

South Asian (SAS)

AF:

0.00

AC:

AN:

2720

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

182

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

37766

Other (OTH)

AF:

0.00

AC:

AN:

1174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.000214

Hom.:

Bravo

AF:

0.0000869

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Martsolf syndrome;C3280214:Warburg micro syndrome 2

Benign:1

Jul 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.5

(source)

DANN

Benign

0.78

PhyloP100

-0.0030

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000068

dbscSNV1_RF

Benign

0.010

SpliceAI score (max)

0.040

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over