1-229508170-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_018230.3(NUP133):c.80C>G(p.Ser27Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000017 in 1,591,882 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 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

NUP133
NM_018230.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.44

Variant links:

Genes affected

NUP133 (HGNC:18016): (nucleoporin 133) The nuclear envelope creates distinct nuclear and cytoplasmic compartments in eukaryotic cells. It consists of two concentric membranes perforated by nuclear pores, large protein complexes that form aqueous channels to regulate the flow of macromolecules between the nucleus and the cytoplasm. These complexes are composed of at least 100 different polypeptide subunits, many of which belong to the nucleoporin family. The nucleoporin protein encoded by this gene displays evolutionarily conserved interactions with other nucleoporins. This protein, which localizes to both sides of the nuclear pore complex at interphase, remains associated with the complex during mitosis and is targeted at early stages to the reforming nuclear envelope. This protein also localizes to kinetochores of mitotic cells. [provided by RefSeq, Jul 2008]

NUP133 links:

NUP133-DT (HGNC:55870): (NUP133 divergent transcript)

NUP133-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity NU133_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27013004).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUP133	NM_018230.3 link	c.80C>G	p.Ser27Cys	missense_variant	Exon 1 of 26	ENST00000261396.6	NP_060700.2	Q8WUM0
NUP133	XM_047424979.1 link	c.80C>G	p.Ser27Cys	missense_variant	Exon 1 of 19		XP_047280935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NUP133	ENST00000261396.6 link	c.80C>G	p.Ser27Cys	missense_variant	Exon 1 of 26	1	NM_018230.3	ENSP00000261396.3	Q8WUM0
NUP133	ENST00000366678.4 link	n.157C>G		non_coding_transcript_exon_variant	Exon 1 of 6	5
NUP133-DT	ENST00000417605.2 link	n.-199G>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000282

AC:

AN:

212750

Hom.:

AF XY:

0.0000339

AC XY:

AN XY:

118106

show subpopulations

Gnomad AFR exome

AF:

0.000267

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:

0.000151

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000139

AC:

AN:

1439630

Hom.:

Cov.:

AF XY:

0.0000182

AC XY:

AN XY:

715252

show subpopulations

Gnomad4 AFR exome

AF:

0.000124

Gnomad4 AMR exome

AF:

0.0000477

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000175

Gnomad4 NFE exome

AF:

9.07e-7

Gnomad4 OTH exome

AF:

0.0000506

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.000169

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000364

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000334

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.80C>G (p.S27C) alteration is located in exon 1 (coding exon 1) of the NUP133 gene. This alteration results from a C to G substitution at nucleotide position 80, causing the serine (S) at amino acid position 27 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Aug 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with NUP133-related conditions. 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. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is present in population databases (rs745951330, gnomAD 0.03%). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 27 of the NUP133 protein (p.Ser27Cys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.71

M_CAP

Benign

0.056

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.83

REVEL

Benign

0.074

Sift

Uncertain

0.016

Sift4G

Uncertain

0.028

Polyphen

0.84

Vest4

0.47

MutPred

0.16

Loss of phosphorylation at S27 (P = 0.005);

MVP

0.55

MPC

0.62

ClinPred

0.44

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.42

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