rs13128486

Variant names:

• chr4-139454142-C-G
• rs13128486
• NM_031296.3:c.-54C>G

Your query was ambiguous. Multiple possible variants found:

• chr4-139454142-C-G
• chr4-139454142-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031296.3(RAB33B):​c.-54C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,552,520 control chromosomes in the GnomAD database, including 47,491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3518 hom., cov: 32)
  • Exomes 𝑓: 0.25 (43973 hom.)
• Consequence: RAB33B NM_031296.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0850
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 4-139454142-C-G is Benign according to our data. Variant chr4-139454142-C-G is described in ClinVar as Benign. ClinVar VariationId is 347558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB33B	NM_031296.3	c.-54C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	ENST00000305626.6	NP_112586.1
RAB33B	NM_031296.3	c.-54C>G		5_prime_UTR_variant	Exon 1 of 2	ENST00000305626.6	NP_112586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB33B	ENST00000305626.6	c.-54C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	1	NM_031296.3	ENSP00000306496.5
RAB33B	ENST00000305626.6	c.-54C>G		5_prime_UTR_variant	Exon 1 of 2	1	NM_031296.3	ENSP00000306496.5

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31142 AN: 152034 Hom.: 3513 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.206

GnomAD4 exome AF: 0.247 AC: 345815 AN: 1400370 Hom.: 43973 Cov.: 31 AF XY: 0.246 AC XY: 169774 AN XY: 690104

African (AFR) AF: 0.121 AC: 3848 AN: 31820

American (AMR) AF: 0.121 AC: 4617 AN: 38080

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 4560 AN: 22054

East Asian (EAS) AF: 0.168 AC: 6572 AN: 39018

South Asian (SAS) AF: 0.197 AC: 15037 AN: 76342

European-Finnish (FIN) AF: 0.242 AC: 12036 AN: 49832

Middle Eastern (MID) AF: 0.226 AC: 982 AN: 4352

European-Non Finnish (NFE) AF: 0.263 AC: 284470 AN: 1081300

Other (OTH) AF: 0.238 AC: 13693 AN: 57572

GnomAD4 genome AF: 0.205 AC: 31149 AN: 152150 Hom.: 3518 Cov.: 32 AF XY: 0.203 AC XY: 15090 AN XY: 74382

African (AFR) AF: 0.122 AC: 5086 AN: 41538

American (AMR) AF: 0.163 AC: 2493 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 736 AN: 3468

East Asian (EAS) AF: 0.190 AC: 979 AN: 5162

South Asian (SAS) AF: 0.196 AC: 947 AN: 4832

European-Finnish (FIN) AF: 0.240 AC: 2544 AN: 10598

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17676 AN: 67948

Other (OTH) AF: 0.210 AC: 444 AN: 2110

Alfa AF: 0.135 Hom.: 243

Bravo AF: 0.196

Asia WGS AF: 0.221 AC: 771 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Smith-McCort dysplasia 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	11
DANN	Benign	0.80
PhyloP100		0.085
PromoterAI		-0.040	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs13128486; hg19: chr4-140375296; COSMIC: COSV59777411; COSMIC: COSV59777411;