4-139454160-C-T

Position:

• chr4-139454160-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_031296.3(RAB33B):​c.-36C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,583,634 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0083 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (10 hom.)
• Consequence: RAB33B NM_031296.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.19

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 4-139454160-C-T is Benign according to our data. Variant chr4-139454160-C-T is described in ClinVar as [Benign]. Clinvar id is 347560.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00834 (1270/152296) while in subpopulation AFR AF= 0.0293 (1219/41578). AF 95% confidence interval is 0.028. There are 20 homozygotes in gnomad4. There are 600 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB33B	NM_031296.3	c.-36C>T		5_prime_UTR_variant	1/2	ENST00000305626.6	NP_112586.1
RAB33B	XM_011532299.2	c.126-17C>T		intron_variant			XP_011530601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB33B	ENST00000305626	c.-36C>T		5_prime_UTR_variant	1/2	1	NM_031296.3	ENSP00000306496.5
RAB33B	ENST00000652268.1	c.126-17C>T		intron_variant				ENSP00000498778.1
RAB33B	ENST00000507271.1	n.467-17C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00833 AC: 1268 AN: 152178 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

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: 0.0000882

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00225 AC: 509 AN: 225994 Hom.: 6 AF XY: 0.00169 AC XY: 206 AN XY: 122094

Gnomad AFR exome AF: 0.0307

Gnomad AMR exome AF: 0.000721

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000155

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000780

Gnomad OTH exome AF: 0.000926

GnomAD4 exome AF: 0.000856 AC: 1225 AN: 1431338 Hom.: 10 Cov.: 32 AF XY: 0.000729 AC XY: 517 AN XY: 709048

Gnomad4 AFR exome AF: 0.0308

Gnomad4 AMR exome AF: 0.00100

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000135

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000584

Gnomad4 OTH exome AF: 0.00165

GnomAD4 genome AF: 0.00834 AC: 1270 AN: 152296 Hom.: 20 Cov.: 32 AF XY: 0.00806 AC XY: 600 AN XY: 74476

Gnomad4 AFR AF: 0.0293

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00443 Hom.: 3

Bravo AF: 0.00963

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Smith-McCort dysplasia 2 Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.1
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs182647425; hg19: chr4-140375314;