rs144455066

chr2-135164663-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_012233.3(RAB3GAP1):c.2676G>T(p.Arg892Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000563 in 1,612,968 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R892G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (3 hom.)
• Consequence: RAB3GAP1 NM_012233.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.171

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005790174).
• BP6: Variant 2-135164663-G-T is Benign according to our data. Variant chr2-135164663-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211980.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00276 (420/152234) while in subpopulation AFR AF= 0.00987 (410/41538). AF 95% confidence interval is 0.00908. There are 1 homozygotes in gnomad4. There are 201 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB3GAP1	NM_012233.3	c.2676G>T	p.Arg892Ser	missense_variant	23/24	ENST00000264158.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB3GAP1	ENST00000264158.13	c.2676G>T	p.Arg892Ser	missense_variant	23/24	1	NM_012233.3	A1

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 420 AN: 152116 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00990

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000785 AC: 197 AN: 250994 Hom.: 1 AF XY: 0.000531 AC XY: 72 AN XY: 135658

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000334 AC: 488 AN: 1460734 Hom.: 3 Cov.: 31 AF XY: 0.000282 AC XY: 205 AN XY: 726732

Gnomad4 AFR exome AF: 0.0128

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.00276 AC: 420 AN: 152234 Hom.: 1 Cov.: 32 AF XY: 0.00270 AC XY: 201 AN XY: 74428

Gnomad4 AFR AF: 0.00987

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000541 Hom.: 0

Bravo AF: 0.00336

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000923 AC: 112

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 26, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 2023	- -

RAB3GAP1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	12
Dann	Benign	0.96
DEOGEN2	Benign	0.040	T;.;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.81	T;T;T
MetaRNN	Benign	0.0058	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.2	N;N;.
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.25	N;N;N
REVEL	Benign	0.14
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.80	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.18
MutPred		0.37		Loss of MoRF binding (P = 0.0283);Loss of MoRF binding (P = 0.0283);.;
MVP		0.28
MPC		0.25
ClinPred		0.0065	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.079
gMVP		0.32

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: rs144455066; hg19: chr2-135922233; COSMIC: COSV104383855; COSMIC: COSV104383855;