1-220148855-A-AAGTT

Position:

• chr1-220148855-A-AAGTT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_012414.4(RAB3GAP2):​c.*2395_*2396insAACT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 152,286 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: RAB3GAP2 NM_012414.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.627

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00217 (330/152286) while in subpopulation AMR AF= 0.00817 (125/15294). AF 95% confidence interval is 0.00701. There are 1 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB3GAP2	NM_012414.4	c.*2395_*2396insAACT		3_prime_UTR_variant	35/35	ENST00000358951.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB3GAP2	ENST00000358951.7	c.*2395_*2396insAACT		3_prime_UTR_variant	35/35	1	NM_012414.4	P2

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 331 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.00923

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00813

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.00217 AC: 330 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74460

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00817

Gnomad4 ASJ AF: 0.00923

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00272

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Warburg micro syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Martsolf syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs552063647; hg19: chr1-220322197;