chr1-220196403-T-TA

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_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
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: 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.

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.812-6dupT		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.812-6_812-5insT		splice_region intron	N/A	ENSP00000351832.2
	RAB3GAP2	ENST00000692972.1		c.887-6_887-5insT		splice_region intron	N/A	ENSP00000510753.1
	RAB3GAP2	ENST00000691661.1		c.824-6_824-5insT		splice_region intron	N/A	ENSP00000510185.1

Frequencies

GnomAD3 genomes AF: 0.000419 AC: 61 AN: 145564 Hom.: 0 Cov.: 21

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

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.: 0 Cov.: 0 AF XY: 0.0446 AC XY: 22795 AN XY: 511182

⚠️ 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.

GnomAD4 genome AF: 0.000433 AC: 63 AN: 145626 Hom.: 0 Cov.: 21 AF XY: 0.000438 AC XY: 31 AN XY: 70772

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

African (AFR) AF: 0.000453 AC: 18 AN: 39700

American (AMR) AF: 0.00 AC: 0 AN: 14706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3356

East Asian (EAS) AF: 0.000198 AC: 1 AN: 5060

South Asian (SAS) AF: 0.00130 AC: 6 AN: 4624

European-Finnish (FIN) AF: 0.00152 AC: 14 AN: 9218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.000365 AC: 24 AN: 65794

Other (OTH) AF: 0.00 AC: 0 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.

Alfa AF: 0.0524 Hom.: 306

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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 v4.9

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

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

Other links and lift over

dbSNP: rs35396665; hg19: chr1-220369745; COSMIC: COSV52965342; COSMIC: COSV52965342;