1-229444994-C-T
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_018230.3(NUP133):c.3254G>A(p.Ser1085Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,608,664 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
NUP133
NM_018230.3 missense
NM_018230.3 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: 5.41
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 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=0.09108403).
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000158 (23/1456498) while in subpopulation EAS AF= 0.00053 (21/39596). AF 95% confidence interval is 0.000355. There are 0 homozygotes in gnomad4_exome. There are 13 alleles in male gnomad4_exome subpopulation. Median coverage is 28. 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 |
---|---|---|---|---|---|---|---|---|
NUP133 | NM_018230.3 | c.3254G>A | p.Ser1085Asn | missense_variant | 25/26 | ENST00000261396.6 | NP_060700.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NUP133 | ENST00000261396.6 | c.3254G>A | p.Ser1085Asn | missense_variant | 25/26 | 1 | NM_018230.3 | ENSP00000261396 | P1 | |
NUP133 | ENST00000490352.1 | n.301G>A | non_coding_transcript_exon_variant | 3/4 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000644 AC: 16AN: 248320Hom.: 0 AF XY: 0.0000820 AC XY: 11AN XY: 134138
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GnomAD4 exome AF: 0.0000158 AC: 23AN: 1456498Hom.: 0 Cov.: 28 AF XY: 0.0000179 AC XY: 13AN XY: 724554
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74322
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 17, 2023 | The c.3254G>A (p.S1085N) alteration is located in exon 25 (coding exon 25) of the NUP133 gene. This alteration results from a G to A substitution at nucleotide position 3254, causing the serine (S) at amino acid position 1085 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Uncertain
T
Polyphen
B
Vest4
MutPred
Loss of phosphorylation at S1085 (P = 0.0412);
MVP
MPC
ClinPred
T
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at