4-139454292-A-C

Position:

chr4-139454292-A-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_031296.3(RAB33B):c.97A>C(p.Ile33Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00022 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

RAB33B
NM_031296.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.06

Variant links:

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 links:

RAB33B (HGNC:):

RAB33B links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16164756).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000854 (13/152184) while in subpopulation NFE AF= 0.000162 (11/68028). AF 95% confidence interval is 0.0000905. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB33B	NM_031296.3 linkuse as main transcript	c.97A>C	p.Ile33Leu	missense_variant	1/2	ENST00000305626.6	NP_112586.1	Q9H082
RAB33B	XM_011532299.2 linkuse as main transcript	c.241A>C	p.Ile81Leu	missense_variant	2/3		XP_011530601.1	A0A494C0Z5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RAB33B	ENST00000305626.6 linkuse as main transcript	c.97A>C	p.Ile33Leu	missense_variant	1/2	1	NM_031296.3	ENSP00000306496.5	Q9H082
RAB33B	ENST00000652268.1 linkuse as main transcript	c.241A>C	p.Ile81Leu	missense_variant	2/3			ENSP00000498778.1	A0A494C0Z5
RAB33B	ENST00000507271.1 linkuse as main transcript	n.*7A>C		downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000796

AC:

AN:

251186

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000234

AC:

342

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

149

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000276

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000106

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 27, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 33 of the RAB33B protein (p.Ile33Leu). This variant is present in population databases (rs766581102, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RAB33B-related conditions. ClinVar contains an entry for this variant (Variation ID: 1416837). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Benign

0.92

DEOGEN2

Benign

0.024

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.061

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.074

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.69

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.38

Sift

Benign

1.0

Sift4G

Benign

0.90

Polyphen

0.10

Vest4

0.20

MVP

0.56

MPC

0.70

ClinPred

0.14

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.77

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over