chr4-139454003-G-T

Variant names:

• chr4-139454003-G-T
• rs886059075
• ENST00000652268.1:c.126-174G>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.126-174G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 513,828 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 0.00023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: RAB33B ENST00000652268.1 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00023 (35/152268) while in subpopulation NFE AF = 0.000412 (28/68006). AF 95% confidence interval is 0.000293. There are 0 homozygotes in GnomAd4. There are 17 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.39C>A		non_coding_transcript_exon	Exon 1 of 2
	RAB33B-AS1	NR_159964.1		n.39C>A		non_coding_transcript_exon	Exon 1 of 1
	RAB33B	NM_031296.3	MANE Select	c.-193G>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.126-174G>T		intron	N/A	ENSP00000498778.1	A0A494C0Z5
	RAB33B	ENST00000873886.1		c.-20+69G>T		intron	N/A	ENSP00000543945.1
	RAB33B	ENST00000930373.1		c.-20+155G>T		intron	N/A	ENSP00000600432.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000429 AC: 155 AN: 361560 Hom.: 0 Cov.: 5 AF XY: 0.000508 AC XY: 94 AN XY: 184906

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

American (AMR) AF: 0.000143 AC: 1 AN: 7016

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 21444

South Asian (SAS) AF: 0.000388 AC: 7 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: 0.000574 AC: 144 AN: 250918

Other (OTH) AF: 0.000145 AC: 3 AN: 20642

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152268 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74444

African (AFR) AF: 0.000120 AC: 5 AN: 41562

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000246

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	-0.77
CADD	Benign	0.32
DANN	Benign	0.87
PhyloP100		-1.0
PromoterAI		0.0026	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;