Genetic Variant NM_012414.4:c.812-7_812-6delTT (chr1-220196403-TAA-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_012414.4(RAB3GAP2):c.812-7_812-6delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00052 in 1,342,468 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000069 ( 0 hom., cov: 21)

Exomes 𝑓: 0.00057 ( 0 hom. )

Consequence

RAB3GAP2
NM_012414.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.214

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: 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 -8 ACMG points.

BP6

Variant 1-220196403-TAA-T is Benign according to our data. Variant chr1-220196403-TAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.812-7_812-6delTT		splice_region intron	N/A	NP_036546.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RAB3GAP2	ENST00000358951.7	TSL:1 MANE Select	c.812-7_812-6delTT	splice_region intron	N/A	ENSP00000351832.2	Q9H2M9-1
RAB3GAP2	ENST00000692972.1		c.887-7_887-6delTT	splice_region intron	N/A	ENSP00000510753.1	A0A8I5KZB3
RAB3GAP2	ENST00000691661.1		c.824-7_824-6delTT	splice_region intron	N/A	ENSP00000510185.1	A0A8I5KYQ0

Frequencies

GnomAD3 genomes

AF:

0.0000686

AC:

AN:

145680

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000757

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000591

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000455

Gnomad OTH

AF:

0.000504

GnomAD2 exomes

AF:

0.00111

AC:

181

AN:

162398

AF XY:

0.00110

show subpopulations

Gnomad AFR exome

AF:

0.0000913

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.000617

Gnomad EAS exome

AF:

0.00227

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.000800

GnomAD4 exome

AF:

0.000575

AC:

688

AN:

1196726

Hom.:

AF XY:

0.000525

AC XY:

314

AN XY:

597972

show subpopulations

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

African (AFR)

AF:

0.000735

AC:

AN:

27200

American (AMR)

AF:

0.00113

AC:

AN:

37888

Ashkenazi Jewish (ASJ)

AF:

0.000189

AC:

AN:

21112

East Asian (EAS)

AF:

0.00106

AC:

AN:

34020

South Asian (SAS)

AF:

0.000416

AC:

AN:

72184

European-Finnish (FIN)

AF:

0.000746

AC:

AN:

44250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4930

European-Non Finnish (NFE)

AF:

0.000539

AC:

488

AN:

905228

Other (OTH)

AF:

0.000681

AC:

AN:

49914

⚠️ 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: 0.285

Heterozygous variant carriers

181

272

362

453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.0000686

AC:

AN:

145742

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

70832

show subpopulations

African (AFR)

AF:

0.0000755

AC:

AN:

39714

American (AMR)

AF:

0.00

AC:

AN:

14712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3358

East Asian (EAS)

AF:

0.000593

AC:

AN:

5060

South Asian (SAS)

AF:

0.00

AC:

AN:

4626

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9248

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.0000456

AC:

AN:

65852

Other (OTH)

AF:

0.000501

AC:

AN:

1998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

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:

0.00148

Hom.:

306

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Martsolf syndrome;C3280214:Warburg micro syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.21

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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