ENST00000652268.1:c.125+136G>A

Variant names:

• chr4-139453833-G-A
• rs535498698
• ENST00000873886.1:c.-121G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000652268.1(RAB33B):​c.125+136G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00386 in 180,866 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: RAB33B ENST00000652268.1 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0530
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0045 (685/152326) while in subpopulation AFR AF = 0.0147 (612/41580). AF 95% confidence interval is 0.0138. There are 6 homozygotes in GnomAd4. There are 329 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
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.209C>T		non_coding_transcript_exon	Exon 1 of 2
	RAB33B-AS1	NR_159964.1		n.209C>T		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB33B	ENST00000873886.1		c.-121G>A		5_prime_UTR	Exon 1 of 3	ENSP00000543945.1
	RAB33B	ENST00000930373.1		c.-35G>A		5_prime_UTR	Exon 1 of 3	ENSP00000600432.1
	RAB33B	ENST00000652268.1		c.125+136G>A		intron	N/A	ENSP00000498778.1	A0A494C0Z5

Frequencies

GnomAD3 genomes AF: 0.00451 AC: 686 AN: 152208 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.000491 AC: 14 AN: 28540 Hom.: 0 Cov.: 0 AF XY: 0.000552 AC XY: 8 AN XY: 14498

African (AFR) AF: 0.00822 AC: 7 AN: 852

American (AMR) AF: 0.00338 AC: 2 AN: 592

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 3 AN: 1074

East Asian (EAS) AF: 0.00 AC: 0 AN: 1638

South Asian (SAS) AF: 0.00 AC: 0 AN: 1060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 164

European-Non Finnish (NFE) AF: 0.0000509 AC: 1 AN: 19650

Other (OTH) AF: 0.000506 AC: 1 AN: 1976

GnomAD4 genome AF: 0.00450 AC: 685 AN: 152326 Hom.: 6 Cov.: 33 AF XY: 0.00442 AC XY: 329 AN XY: 74494

African (AFR) AF: 0.0147 AC: 612 AN: 41580

American (AMR) AF: 0.00189 AC: 29 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68026

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00347 Hom.: 0

Bravo AF: 0.00508

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	-0.62
CADD	Benign	17
DANN	Benign	0.86
PhyloP100		0.053
PromoterAI		-0.15	Neutral
Mutation Taster		=300/0	polymorphism

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: rs535498698; hg19: chr4-140374987;