NM_012233.3:c.2946A>G

Variant names:

• chr2-135168781-A-G
• rs141436429
• NM_012233.3:c.2946A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM4 BS1_Supporting

The NM_012233.3(RAB3GAP1):​c.2946A>G​(p.Ter982Trpext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000475 in 1,610,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: RAB3GAP1 NM_012233.3 stop_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 2.71

Genes affected

RAB3GAP1 (HGNC:17063): (RAB3 GTPase activating protein catalytic subunit 1) This gene encodes the catalytic subunit of a Rab GTPase activating protein. The encoded protein forms a heterodimer with a non-catalytic subunit to specifically regulate the activity of members of the Rab3 subfamily of small G proteins. This protein mediates the hydrolysis of GTP bound Rab3 to the GDP bound form. Mutations in this gene are associated with Warburg micro syndrome. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Feb 2010]

ZRANB3 (HGNC:25249): (zinc finger RANBP2-type containing 3) Enables ATP-dependent DNA/DNA annealing activity; K63-linked polyubiquitin modification-dependent protein binding activity; and endodeoxyribonuclease activity. Involved in several processes, including DNA metabolic process; DNA rewinding; and negative regulation of DNA recombination. Located in nuclear replication fork and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_012233.3 Downstream stopcodon found after 986 codons.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000503 (734/1458316) while in subpopulation NFE AF= 0.000616 (683/1108800). AF 95% confidence interval is 0.000577. There are 0 homozygotes in gnomad4_exome. There are 357 alleles in male gnomad4_exome subpopulation. Median coverage is 30. 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 rank	MANE	Protein	UniProt
RAB3GAP1	NM_012233.3	c.2946A>G	p.Ter982Trpext*?	stop_lost	Exon 24 of 24	ENST00000264158.13	NP_036365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB3GAP1	ENST00000264158.13	c.2946A>G	p.Ter982Trpext*?	stop_lost	Exon 24 of 24	1	NM_012233.3	ENSP00000264158.8

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000187 AC: 47 AN: 251376 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135856

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000503 AC: 734 AN: 1458316 Hom.: 0 Cov.: 30 AF XY: 0.000492 AC XY: 357 AN XY: 725888

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000616

Gnomad4 OTH exome AF: 0.000663

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74290

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000408 Hom.: 0

Bravo AF: 0.000298

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5

Jul 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change disrupts the translational stop signal of the RAB3GAP1 mRNA. It is expected to extend the length of the RAB3GAP1 protein by 3 additional amino acid residues. This variant is present in population databases (rs141436429, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with RAB3GAP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 436467). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jul 24, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Normal stop codon changed to a tryptophan codon, leading to the addition of 3 amino acids at the C-terminus; Has not been previously published as pathogenic or benign to our knowledge -

Apr 23, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM4 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Uncertain:2

Jan 06, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 24, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RAB3GAP1 c.2946A>G (p.X982TrpextX3) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. RAB3GAP1 c.2946A>G (p.X982TrpextX3) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 0.00019 in 251376 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RAB3GAP1 causing RAB3GAP1-Related Disorders, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2946A>G in individuals affected with RAB3GAP1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 436467). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Warburg micro syndrome 1;C5543626:Martsolf syndrome 2 Uncertain:1

Mar 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Warburg micro syndrome 1 Uncertain:1

Nov 26, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RAB3GAP1 c.2946A>G (p.Ter982TrpextTer3) variant is a stop-lost variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.000348 in the European (non-Finnish) population from the Genome Aggregation Database. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of stop-lost variants and lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for Warburg micro syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.76
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.71	D
Vest4		0.074
GERP RS		-2.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs141436429; hg19: chr2-135926351;