Genetic Variant RAB3GAP2:c.812-6dupT (chr1-220196403-T-TA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP6_Moderate

The NM_012414.4(RAB3GAP2):c.812-6dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0402 in 1,175,140 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 21)

Exomes 𝑓: 0.046 ( 0 hom. )

Consequence

RAB3GAP2
NM_012414.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.00300

Publications

4 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Variant has high frequency in the NFE (0.0475) population. However there is too low homozygotes in high coverage region: (expected more than 474, got 0).

BP6

Variant 1-220196403-T-TA is Benign according to our data. Variant chr1-220196403-T-TA is described in ClinVar as Benign. ClinVar VariationId is 1575669.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB3GAP2	ENST00000358951.7 link	c.812-6_812-5insT		splice_region_variant, intron_variant	Intron 9 of 34	1	NM_012414.4	ENSP00000351832.2

Frequencies

GnomAD3 genomes

AF:

0.000419

AC:

AN:

145564

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000404

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000197

Gnomad SAS

AF:

0.00129

Gnomad FIN

AF:

0.00152

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000365

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0277

AC:

4502

AN:

162398

AF XY:

0.0279

show subpopulations

Gnomad AFR exome

AF:

0.0233

Gnomad AMR exome

AF:

0.0247

Gnomad ASJ exome

AF:

0.0610

Gnomad EAS exome

AF:

0.0164

Gnomad FIN exome

AF:

0.0271

Gnomad NFE exome

AF:

0.0247

Gnomad OTH exome

AF:

0.0448

GnomAD4 exome

AF:

0.0458

AC:

47162

AN:

1029514

Hom.:

Cov.:

AF XY:

0.0446

AC XY:

22795

AN XY:

511182

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0462

AC:

1090

AN:

23574

American (AMR)

AF:

0.0259

AC:

901

AN:

34756

Ashkenazi Jewish (ASJ)

AF:

0.0658

AC:

1074

AN:

16320

East Asian (EAS)

AF:

0.0273

AC:

825

AN:

30172

South Asian (SAS)

AF:

0.0415

AC:

2481

AN:

59764

European-Finnish (FIN)

AF:

0.0348

AC:

1377

AN:

39546

Middle Eastern (MID)

AF:

0.0354

AC:

152

AN:

4292

European-Non Finnish (NFE)

AF:

0.0479

AC:

37274

AN:

778602

Other (OTH)

AF:

0.0468

AC:

1988

AN:

42488

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.248

Heterozygous variant carriers

6956

13912

20867

27823

34779

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

1472

2944

4416

5888

7360

<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:

0.000433

AC:

AN:

145626

Hom.:

Cov.:

AF XY:

0.000438

AC XY:

AN XY:

70772

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000453

AC:

AN:

39700

American (AMR)

AF:

0.00

AC:

AN:

14706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3356

East Asian (EAS)

AF:

0.000198

AC:

AN:

5060

South Asian (SAS)

AF:

0.00130

AC:

AN:

4624

European-Finnish (FIN)

AF:

0.00152

AC:

AN:

9218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.000365

AC:

AN:

65794

Other (OTH)

AF:

0.00

AC:

AN:

1994

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000079972), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.393

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:

0.0524

Hom.:

306

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Martsolf syndrome;C3280214:Warburg micro syndrome 2

Benign:1

May 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.0030

Mutation Taster

=100/0

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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1-220196403-TAAA-TAAAA

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