4-139454003-G-A

Variant names:

• chr4-139454003-G-A
• rs886059075
• ENST00000652268.1:c.126-174G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000652268.1(RAB33B):​c.126-174G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 361,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: RAB33B ENST00000652268.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).

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.39C>T		non_coding_transcript_exon	Exon 1 of 2
	RAB33B-AS1	NR_159964.1		n.39C>T		non_coding_transcript_exon	Exon 1 of 1
	RAB33B	NM_031296.3	MANE Select	c.-193G>A		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.126-174G>A		intron	N/A	ENSP00000498778.1	A0A494C0Z5
	RAB33B	ENST00000873886.1		c.-20+69G>A		intron	N/A	ENSP00000543945.1
	RAB33B	ENST00000930373.1		c.-20+155G>A		intron	N/A	ENSP00000600432.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000277 AC: 1 AN: 361564 Hom.: 0 Cov.: 5 AF XY: 0.00000541 AC XY: 1 AN XY: 184906

African (AFR) AF: 0.00 AC: 0 AN: 7678

American (AMR) AF: 0.00 AC: 0 AN: 7016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9888

East Asian (EAS) AF: 0.0000466 AC: 1 AN: 21444

South Asian (SAS) AF: 0.00 AC: 0 AN: 18062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1582

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 250922

Other (OTH) AF: 0.00 AC: 0 AN: 20642

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.55
DANN	Benign	0.97
PhyloP100		-1.0
PromoterAI		0.011	Neutral

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

Other links and lift over

dbSNP: rs886059075; hg19: chr4-140375157;