rs1085307130

Variant names:

• chr4-139454239-CCAGCGGGG-C
• rs1085307130
• NM_031296.3:c.48_55delCGGGGCAG

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_031296.3(RAB33B):​c.48_55delCGGGGCAG​(p.Gly17ValfsTer59) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAB33B NM_031296.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.54
• Publications: 1 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_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-139454239-CCAGCGGGG-C is Pathogenic according to our data. Variant chr4-139454239-CCAGCGGGG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 425562.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031296.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB33B	NM_031296.3	MANE Select	c.48_55delCGGGGCAG	p.Gly17ValfsTer59	frameshift	Exon 1 of 2	NP_112586.1
	RAB33B-AS1	NR_159963.1		n.-206_-199delCCCCGCTG		upstream_gene	N/A
	RAB33B-AS1	NR_159964.1		n.-206_-199delCCCCGCTG		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB33B	ENST00000305626.6	TSL:1 MANE Select	c.48_55delCGGGGCAG	p.Gly17ValfsTer59	frameshift	Exon 1 of 2	ENSP00000306496.5
	RAB33B	ENST00000652268.1		c.192_199delCGGGGCAG	p.Gly65ValfsTer59	frameshift	Exon 2 of 3	ENSP00000498778.1
	RAB33B	ENST00000507271.1	TSL:4	n.533_540delCGGGGCAG		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Smith-McCort dysplasia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=9/191	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1085307130; hg19: chr4-140375393;