rs35396665

Positions:

• chr1-220196403-TAA-T
• chr1-220196403-TAA-TA
• chr1-220196403-TAA-TAAA
• chr1-220196403-TAA-TAAAA

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP6_Very_Strong

The NM_012414.4(RAB3GAP2):​c.812-7_812-6del variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.214

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-220196403-TAA-T is Benign according to our data. Variant chr1-220196403-TAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 235478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB3GAP2	NM_012414.4	c.812-7_812-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000358951.7	NP_036546.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB3GAP2	ENST00000358951.7	c.812-7_812-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_012414.4	ENSP00000351832	P2

Frequencies

GnomAD3 genomes AF: 0.0000686 AC: 10 AN: 145680 Hom.: 0 Cov.: 21

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

GnomAD4 exome AF: 0.000575 AC: 688 AN: 1196726 Hom.: 0 AF XY: 0.000525 AC XY: 314 AN XY: 597972

Gnomad4 AFR exome AF: 0.000735

Gnomad4 AMR exome AF: 0.00113

Gnomad4 ASJ exome AF: 0.000189

Gnomad4 EAS exome AF: 0.00106

Gnomad4 SAS exome AF: 0.000416

Gnomad4 FIN exome AF: 0.000746

Gnomad4 NFE exome AF: 0.000539

Gnomad4 OTH exome AF: 0.000681

GnomAD4 genome AF: 0.0000686 AC: 10 AN: 145742 Hom.: 0 Cov.: 21 AF XY: 0.0000565 AC XY: 4 AN XY: 70832

Gnomad4 AFR AF: 0.0000755

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000593

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000456

Gnomad4 OTH AF: 0.000501

Alfa AF: 0.00148 Hom.: 306

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	RAB3GAP2: BP4 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 26, 2015	- -

Martsolf syndrome;C3280214:Warburg micro syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs35396665; hg19: chr1-220369745;