chr4-139454032-G-A

Position:

• chr4-139454032-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000652268.1(RAB33B):​c.126-145G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 777,446 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (79 hom.)
• Consequence: RAB33B ENST00000652268.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.179

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 4-139454032-G-A is Benign according to our data. Variant chr4-139454032-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 347555.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.056 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB33B	XM_011532299.2	c.126-145G>A		intron_variant			XP_011530601.1
RAB33B-AS1	NR_159963.1	n.10C>T		non_coding_transcript_exon_variant	1/2
RAB33B-AS1	NR_159964.1	n.10C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB33B	ENST00000652268.1	c.126-145G>A		intron_variant				ENSP00000498778.1
RAB33B-AS1	ENST00000609359.1	n.3C>T		non_coding_transcript_exon_variant	1/3	2
RAB33B	ENST00000507271.1	n.467-145G>A		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 432 AN: 152090 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0618

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000958

GnomAD4 exome AF: 0.00386 AC: 2412 AN: 625246 Hom.: 79 Cov.: 9 AF XY: 0.00378 AC XY: 1208 AN XY: 319558

Gnomad4 AFR exome AF: 0.000290

Gnomad4 AMR exome AF: 0.000150

Gnomad4 ASJ exome AF: 0.000144

Gnomad4 EAS exome AF: 0.0716

Gnomad4 SAS exome AF: 0.00112

Gnomad4 FIN exome AF: 0.00357

Gnomad4 NFE exome AF: 0.000273

Gnomad4 OTH exome AF: 0.00440

GnomAD4 genome AF: 0.00282 AC: 429 AN: 152200 Hom.: 8 Cov.: 33 AF XY: 0.00321 AC XY: 239 AN XY: 74414

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0616

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.00271

Asia WGS AF: 0.0310 AC: 107 AN: 3474

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Smith-McCort dysplasia Benign:1

Likely 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	-0.79
CADD	Benign	7.3
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs76593161; hg19: chr4-140375186;