1-220196403-TAAA-TAA

Variant names:

• chr1-220196403-TA-T
• rs35396665
• NM_012414.4:c.812-6delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_012414.4(RAB3GAP2):​c.812-6delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 1,241,496 control chromosomes in the GnomAD database, including 21,623 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5009 hom., cov: 21)
  • Exomes 𝑓: 0.29 (16614 hom.)
• Consequence: RAB3GAP2 NM_012414.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.00300
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-220196403-TA-T is Benign according to our data. Variant chr1-220196403-TA-T is described in ClinVar as Benign. ClinVar VariationId is 295665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB3GAP2	NM_012414.4	MANE Select	c.812-6delT		splice_region intron	N/A	NP_036546.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB3GAP2	ENST00000358951.7	TSL:1 MANE Select	c.812-6delT		splice_region intron	N/A	ENSP00000351832.2
	RAB3GAP2	ENST00000692972.1		c.887-6delT		splice_region intron	N/A	ENSP00000510753.1
	RAB3GAP2	ENST00000691661.1		c.824-6delT		splice_region intron	N/A	ENSP00000510185.1

Frequencies

GnomAD3 genomes AF: 0.265 AC: 38504 AN: 145470 Hom.: 5003 Cov.: 21

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.239

GnomAD2 exomes AF: 0.379 AC: 61612 AN: 162398 AF XY: 0.377

Gnomad AFR exome AF: 0.340

Gnomad AMR exome AF: 0.478

Gnomad ASJ exome AF: 0.325

Gnomad EAS exome AF: 0.451

Gnomad FIN exome AF: 0.384

Gnomad NFE exome AF: 0.342

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.293 AC: 320888 AN: 1095966 Hom.: 16614 Cov.: 0 AF XY: 0.292 AC XY: 159599 AN XY: 546122

African (AFR) AF: 0.300 AC: 7513 AN: 25026

American (AMR) AF: 0.415 AC: 14824 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 4026 AN: 18162

East Asian (EAS) AF: 0.383 AC: 12213 AN: 31874

South Asian (SAS) AF: 0.299 AC: 19238 AN: 64250

European-Finnish (FIN) AF: 0.335 AC: 13705 AN: 40944

Middle Eastern (MID) AF: 0.252 AC: 1141 AN: 4520

European-Non Finnish (NFE) AF: 0.283 AC: 234720 AN: 829984

Other (OTH) AF: 0.297 AC: 13508 AN: 45506

GnomAD4 genome AF: 0.265 AC: 38541 AN: 145530 Hom.: 5009 Cov.: 21 AF XY: 0.269 AC XY: 19037 AN XY: 70706

African (AFR) AF: 0.258 AC: 10214 AN: 39662

American (AMR) AF: 0.322 AC: 4735 AN: 14696

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 479 AN: 3352

East Asian (EAS) AF: 0.390 AC: 1970 AN: 5056

South Asian (SAS) AF: 0.244 AC: 1125 AN: 4620

European-Finnish (FIN) AF: 0.312 AC: 2870 AN: 9204

Middle Eastern (MID) AF: 0.204 AC: 57 AN: 280

European-Non Finnish (NFE) AF: 0.248 AC: 16341 AN: 65772

Other (OTH) AF: 0.242 AC: 483 AN: 1994

Alfa AF: 0.192 Hom.: 306

Bravo AF: 0.261

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Warburg micro syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Martsolf syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

May 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.0030
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35396665; hg19: chr1-220369745;