chr1-229441971-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_018230.3(NUP133):​c.3404A>C​(p.Lys1135Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

NUP133
NM_018230.3 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.25
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.319646).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NUP133NM_018230.3 linkuse as main transcriptc.3404A>C p.Lys1135Thr missense_variant 26/26 ENST00000261396.6 NP_060700.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NUP133ENST00000261396.6 linkuse as main transcriptc.3404A>C p.Lys1135Thr missense_variant 26/261 NM_018230.3 ENSP00000261396 P1
NUP133ENST00000490352.1 linkuse as main transcriptn.451A>C non_coding_transcript_exon_variant 4/42

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 06, 2022In 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with NUP133-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 1135 of the NUP133 protein (p.Lys1135Thr). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.073
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
T
Eigen
Benign
0.11
Eigen_PC
Uncertain
0.22
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.88
D
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.32
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.1
M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-2.3
N
REVEL
Benign
0.095
Sift
Uncertain
0.015
D
Sift4G
Uncertain
0.018
D
Polyphen
0.63
P
Vest4
0.37
MutPred
0.34
Loss of methylation at K1135 (P = 0.0034);
MVP
0.50
MPC
0.47
ClinPred
0.93
D
GERP RS
5.6
Varity_R
0.14
gMVP
0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-229577718; API