4-139454142-C-G

Position:

• chr4-139454142-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031296.3(RAB33B):​c.-54C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,552,520 control chromosomes in the GnomAD database, including 47,491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3518 hom., cov: 32)
  • Exomes 𝑓: 0.25 (43973 hom.)
• Consequence: RAB33B NM_031296.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0850

Genes affected

RAB33B (HGNC:16075): (RAB33B, member RAS oncogene family) This gene encodes a small GTP-binding protein of the Rab GTPase family, whose members function in vesicle transport during protein secretion and endocytosis. Rab GTPases are active, membrane-associated proteins that recruit effector proteins in the GTP-bound state and inactive cytosolic proteins when in a GDP-bound state. The protein encoded by this gene is ubiquitously expressed and has been implicated in Golgi to endoplasmic reticulum cycling of Golgi enzymes. In addition, this protein regulates Golgi homeostasis and coordinates intra-Golgi retrograde trafficking. Allelic variants in this gene have been associated with Dyggve-Melchior-Clausen syndrome and Smith-McCort dysplasia 2, which are autosomal recessive spondyloepimetaphyseal dysplasias characterized by skeletal abnormalities. [provided by RefSeq, Sep 2016]

RAB33B (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 4-139454142-C-G is Benign according to our data. Variant chr4-139454142-C-G is described in ClinVar as [Benign]. Clinvar id is 347558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB33B	NM_031296.3	c.-54C>G		5_prime_UTR_premature_start_codon_gain_variant	1/2	ENST00000305626.6	NP_112586.1
RAB33B	NM_031296.3	c.-54C>G		5_prime_UTR_variant	1/2	ENST00000305626.6	NP_112586.1
RAB33B	XM_011532299.2	c.126-35C>G		intron_variant			XP_011530601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB33B	ENST00000305626	c.-54C>G		5_prime_UTR_premature_start_codon_gain_variant	1/2	1	NM_031296.3	ENSP00000306496.5
RAB33B	ENST00000305626	c.-54C>G		5_prime_UTR_variant	1/2	1	NM_031296.3	ENSP00000306496.5
RAB33B	ENST00000652268.1	c.126-35C>G		intron_variant				ENSP00000498778.1
RAB33B	ENST00000507271.1	n.467-35C>G		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31142 AN: 152034 Hom.: 3513 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.206

GnomAD4 exome AF: 0.247 AC: 345815 AN: 1400370 Hom.: 43973 Cov.: 31 AF XY: 0.246 AC XY: 169774 AN XY: 690104

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.121

Gnomad4 ASJ exome AF: 0.207

Gnomad4 EAS exome AF: 0.168

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.242

Gnomad4 NFE exome AF: 0.263

Gnomad4 OTH exome AF: 0.238

GnomAD4 genome AF: 0.205 AC: 31149 AN: 152150 Hom.: 3518 Cov.: 32 AF XY: 0.203 AC XY: 15090 AN XY: 74382

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.163

Gnomad4 ASJ AF: 0.212

Gnomad4 EAS AF: 0.190

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.240

Gnomad4 NFE AF: 0.260

Gnomad4 OTH AF: 0.210

Alfa AF: 0.135 Hom.: 243

Bravo AF: 0.196

Asia WGS AF: 0.221 AC: 771 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Smith-McCort dysplasia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	11
DANN	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs13128486; hg19: chr4-140375296; COSMIC: COSV59777411; COSMIC: COSV59777411;