ENST00000652268.1:c.126-144C>T

Variant names:

• chr4-139454033-C-T
• rs886059076
• ENST00000652268.1:c.126-144C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The ENST00000652268.1(RAB33B):​c.126-144C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 775,164 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 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: RAB33B ENST00000652268.1 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.06
• Publications: 0 publications found

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-AS1 (HGNC:55153): (RAB33B antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000112 (17/151940) while in subpopulation AFR AF = 0.000411 (17/41408). AF 95% confidence interval is 0.000261. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000652268.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB33B-AS1	NR_159963.1		n.9G>A		non_coding_transcript_exon	Exon 1 of 2
	RAB33B-AS1	NR_159964.1		n.9G>A		non_coding_transcript_exon	Exon 1 of 1
	RAB33B	NM_031296.3	MANE Select	c.-163C>T		upstream_gene	N/A	NP_112586.1	Q9H082

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB33B	ENST00000652268.1		c.126-144C>T		intron	N/A	ENSP00000498778.1	A0A494C0Z5
	RAB33B	ENST00000873886.1		c.-20+99C>T		intron	N/A	ENSP00000543945.1
	RAB33B	ENST00000930373.1		c.-19-144C>T		intron	N/A	ENSP00000600432.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151940 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000411

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 9 AN: 623224 Hom.: 0 Cov.: 8 AF XY: 0.00000942 AC XY: 3 AN XY: 318320

African (AFR) AF: 0.000511 AC: 7 AN: 13690

American (AMR) AF: 0.00 AC: 0 AN: 13280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13878

East Asian (EAS) AF: 0.00 AC: 0 AN: 27784

South Asian (SAS) AF: 0.00 AC: 0 AN: 46268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2250

European-Non Finnish (NFE) AF: 0.00000224 AC: 1 AN: 446234

Other (OTH) AF: 0.0000324 AC: 1 AN: 30822

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151940 Hom.: 0 Cov.: 33 AF XY: 0.000162 AC XY: 12 AN XY: 74204

African (AFR) AF: 0.000411 AC: 17 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000136

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Smith-McCort dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.1
DANN	Benign	0.95
PhyloP100		-3.1
PromoterAI		0.057	Neutral

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

Other links and lift over

dbSNP: rs886059076; hg19: chr4-140375187;