4-139453991-G-C

Position:

• chr4-139453991-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000652268.1(RAB33B):​c.126-186G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 474,664 control chromosomes in the GnomAD database, including 14,373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3503 hom., cov: 33)
  • Exomes 𝑓: 0.25 (10870 hom.)
• Consequence: RAB33B ENST00000652268.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.188

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 4-139453991-G-C is Benign according to our data. Variant chr4-139453991-G-C is described in ClinVar as [Benign]. Clinvar id is 347552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB33B	XM_011532299.2	c.126-186G>C		intron_variant			XP_011530601.1
RAB33B-AS1	NR_159963.1	n.51C>G		non_coding_transcript_exon_variant	1/2
RAB33B-AS1	NR_159964.1	n.51C>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB33B	ENST00000652268.1	c.126-186G>C		intron_variant				ENSP00000498778.1
RAB33B-AS1	ENST00000609359.1	n.44C>G		non_coding_transcript_exon_variant	1/3	2
RAB33B	ENST00000507271.1	n.467-186G>C		intron_variant		4
RAB33B-AS1	ENST00000608661.1	n.-36C>G		upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30969 AN: 152030 Hom.: 3499 Cov.: 33

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.206

GnomAD4 exome AF: 0.254 AC: 81871 AN: 322524 Hom.: 10870 Cov.: 5 AF XY: 0.251 AC XY: 41508 AN XY: 165350

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.149

Gnomad4 ASJ exome AF: 0.208

Gnomad4 EAS exome AF: 0.148

Gnomad4 SAS exome AF: 0.205

Gnomad4 FIN exome AF: 0.244

Gnomad4 NFE exome AF: 0.279

Gnomad4 OTH exome AF: 0.240

GnomAD4 genome AF: 0.204 AC: 30976 AN: 152140 Hom.: 3503 Cov.: 33 AF XY: 0.202 AC XY: 15020 AN XY: 74376

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.161

Gnomad4 ASJ AF: 0.212

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.240

Gnomad4 NFE AF: 0.261

Gnomad4 OTH AF: 0.211

Alfa AF: 0.228 Hom.: 516

Bravo AF: 0.194

Asia WGS AF: 0.221 AC: 769 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Smith-McCort dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.8
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs13126617; hg19: chr4-140375145;