rs150478342

Positions:

• chr2-135130027-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012233.3(RAB3GAP1):​c.1006C>T​(p.Arg336Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 1,611,028 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (35 hom.)
• Consequence: RAB3GAP1 NM_012233.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: 2.61

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010591298).
• BP6: Variant 2-135130027-C-T is Benign according to our data. Variant chr2-135130027-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 211978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0041 (619/151110) while in subpopulation NFE AF= 0.00637 (432/67860). AF 95% confidence interval is 0.00587. There are 2 homozygotes in gnomad4. There are 306 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB3GAP1	NM_012233.3	c.1006C>T	p.Arg336Cys	missense_variant	12/24	ENST00000264158.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB3GAP1	ENST00000264158.13	c.1006C>T	p.Arg336Cys	missense_variant	12/24	1	NM_012233.3	A1

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 619 AN: 150992 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00375

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00292

Gnomad FIN AF: 0.00430

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00637

Gnomad OTH AF: 0.00193

GnomAD3 exomes AF: 0.00430 AC: 1079 AN: 250700 Hom.: 6 AF XY: 0.00433 AC XY: 587 AN XY: 135484

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.00368

Gnomad ASJ exome AF: 0.00467

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.00231

Gnomad FIN exome AF: 0.00500

Gnomad NFE exome AF: 0.00603

Gnomad OTH exome AF: 0.00507

GnomAD4 exome AF: 0.00422 AC: 6164 AN: 1459918 Hom.: 35 Cov.: 31 AF XY: 0.00446 AC XY: 3237 AN XY: 726158

Gnomad4 AFR exome AF: 0.000509

Gnomad4 AMR exome AF: 0.00358

Gnomad4 ASJ exome AF: 0.00625

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.00216

Gnomad4 FIN exome AF: 0.00592

Gnomad4 NFE exome AF: 0.00457

Gnomad4 OTH exome AF: 0.00385

GnomAD4 genome AF: 0.00410 AC: 619 AN: 151110 Hom.: 2 Cov.: 32 AF XY: 0.00415 AC XY: 306 AN XY: 73668

Gnomad4 AFR AF: 0.00109

Gnomad4 AMR AF: 0.00375

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00292

Gnomad4 FIN AF: 0.00430

Gnomad4 NFE AF: 0.00637

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.00579 Hom.: 5

Bravo AF: 0.00353

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00447 AC: 543

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00645

EpiControl AF: 0.00617

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 29, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	RAB3GAP1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2020	This variant is associated with the following publications: (PMID: 29924831) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 06, 2018	- -

Amenorrhea Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Mar 08, 2021

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 20, 2016

- -

Warburg micro syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T;.;.
Eigen	Benign	-0.090
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.70	N;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.0060	B;.;.
Vest4		0.42
MVP		0.78
MPC		0.30
ClinPred		0.013	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150478342; hg19: chr2-135887597; COSMIC: COSV99920844;