GeneBe

NUP98

protein-coding

nucleoporin 98 and 96 precursor, the group of Nucleoporins

Gene summary

Nuclear pore complexes (NPCs) regulate the transport of macromolecules between the nucleus and cytoplasm, and are composed of many polypeptide subunits, many of which belong to the nucleoporin family. This gene belongs to the nucleoporin gene family and encodes a 186 kDa precursor protein that undergoes autoproteolytic cleavage to generate a 98 kDa nucleoporin and 96 kDa nucleoporin. The 98 kDa nucleoporin contains a Gly-Leu-Phe-Gly (GLGF) repeat domain and participates in many cellular processes, including nuclear import, nuclear export, mitotic progression, and regulation of gene expression. The 96 kDa nucleoporin is a scaffold component of the NPC. Proteolytic cleavage is important for targeting of the proteins to the NPC. Translocations between this gene and many other partner genes have been observed in different leukemias. Rearrangements typically result in chimeras with the N-terminal GLGF domain of this gene to the C-terminus of the partner gene. Alternative splicing results in multiple transcript variants encoding different isoforms, at least two of which are proteolytically processed. Some variants lack the region that encodes the 96 kDa nucleoporin. [provided by RefSeq, Feb 2016]

MANE transcript

NM_016320.5

Inheritance

AR

ClinVar variants

P:1U:231B:22

Top phenotype

Hirschsprung disease, susceptibility to, 1

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr11:3,671,083-3,797,792

External References & Databases

Ensembl (ENSG00000110713)NCBI Gene (4928)OMIM (601021)HGNC:8068GenCCUniProt (P52948)AlphaFoldClinVar (NUP98)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~126.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0021094

Submitter: LiferaOmics

Genetic evidence – Published PMID: 31130284 – Families 1–3 – three probands Three probands with variants in NUP98 identified in a large clinical exome sequencing cohort in a consanguineous population. Case-level (non-LOF start = 0.1; missense) = 3 × 0.1 = 0.3; Segregation = 0; Case-control = 0 Families 1–3 total = 0.3 Published genetic evidence total = 0.3 / 12 Genetic evidence – Our cases Family 4 – one proband One proband with recurrent infections harboring NUP98 NM_016320.5:c.3494A>G;p.(Asn1165Ser) Case-level (Homozygous; missense) = 0.1; Segregation = 0; Case-control = 0 Family 4 total = 0.1 Total genetic evidence (published + our cases) 0.3 + 0.1 = 0.4 / 12 Experimental evidence – Published PMID: 23523133 – Functional role in viral infection NUP98 interacts with viral components (HIV-1 capsid/nucleocapsid), supporting a role in viral nuclear import/replication. Functional alteration = 0.5 PMID: 38449868 NUP98 regulates HIV-1 transcription and infectivity (knockdown ↑ replication; overexpression ↓ infectivity). Functional alteration = 0.5 PMID: 41591840 NUP98 directly binds viral RNA and promotes replication of orthoflaviviruses, demonstrating mechanistic involvement in infection biology. Functional alteration = 0.5 NUP98 is recruited to viral replication complexes across multiple viruses (e.g., flaviviruses), supporting a conserved host-factor role. Functional evidence = 0.5 Experimental evidence total = 2.0 / 6 Overall score • Genetic evidence = 0.4 / 12 • Experimental evidence = 2.0 / 6 • Overall score = 2.4 / 18

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NUP98 variants in ClinVar

3 Conditions Cataloged
not specifiedTotal: 219
not providedTotal: 16
Hirschsprung disease, susceptibility to, 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016320.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
3
clinvar
5
clinvar
3
clinvar
 11
missense
1
clinvar
218
clinvar
8
clinvar
6
clinvar
 233
nonsense
0
start loss
0
frameshift
1
clinvar
 1
splice donor/acceptor (+/-2bp)
9
clinvar
 9
Total01231139254

Highest pathogenic variant AF is 0.0000013682305

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 108 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_016320.5RefSeqNP_057404.232MANE Select
ENST00000324932.12EnsemblENSP00000316032.732MANE Select
NM_001365125.2RefSeqNP_001352054.133Standard
NM_001365126.2RefSeqNP_001352055.132Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
nup98Danio rerio

Structure: cerebellar central artery

Quality: hemorrhagic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Influenza A - Homo sapiens (human)
  • RNA transport - Homo sapiens (human)
  • tRNA processing
  • Disease
  • Signal Transduction

Biological Process

  • posttranscriptional tethering of RNA polymerase II gene DNA at nuclear periphery
  • DNA replication
  • RNA export from nucleus
  • mRNA export from nucleus
  • proteolysis

Molecular Function

  • transcription coactivator activity
  • RNA binding
  • mRNA binding
  • transporter activity
  • protein binding

Cellular Component

  • kinetochore
  • nuclear envelope
  • nuclear pore
  • nucleoplasm
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000324932
Coding exons
32
Length
126710
Individuals with no LoFs
125737
Homozygous LoFs
0
Heterozygous LoFs
9
Defined
125746
p
0.0000358
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.418459680.8730.000050911690
Missense (PolyPhen)347464.650.74685774
Synonymous-0.2163513461.010.00001683639
Loss of Function8.11586.40.05790.000004631018

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000530.000053rare
South Asian0.0000360.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance. NUP98 and NUP96 are involved in the bidirectional transport across the NPC. May anchor NUP153 and TPR to the NPC. In cooperation with DHX9, plays a role in transcription and alternative splicing activation of a subset of genes (PubMed:28221134). Involved in the localization of DHX9 in discrete intranuclear foci (GLFG-body) (PubMed:28221134). {ECO:0000269|PubMed:15229283}.;
Disease
DISEASE: Note=A chromosomal aberration involving NUP98 is found in a form of acute myeloid leukemia. Translocation t(7;11)(p15;p15) with HOXA9. Translocation t(11;17)(p15;p13) with PHF23. {ECO:0000269|PubMed:16028218}.; DISEASE: Note=A chromosomal aberration involving NUP98 is found in childhood acute myeloid leukemia. Translocation t(5;11)(q35;p15.5) with NSD1. Translocation t(8;11)(p11.2;p15) with WHSC1L1. {ECO:0000269|PubMed:16028218}.; DISEASE: Note=A chromosomal aberration involving NUP98 is found in a form of therapy-related myelodysplastic syndrome. Translocation t(11;20)(p15;q11) with TOP1. {ECO:0000269|PubMed:16028218}.; DISEASE: Note=A chromosomal aberration involving NUP98 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(3;11)(q12.2;p15.4) with LNP1. {ECO:0000269|PubMed:16028218}.; DISEASE: Note=A chromosomal aberration involving NUP98 is associated with pediatric acute myeloid leukemia (AML) with intermediate characteristics between M2-M3 French-American-British (FAB) subtypes. Translocation t(9;11)(p22;p15) with PSIP1/LEDGF. The chimeric transcript is an in-frame fusion of NUP98 exon 8 to PSIP1/LEDGF exon 4. {ECO:0000269|PubMed:16028218}.; DISEASE: Note=A chromosomal aberration involving NUP98 has been identified in acute leukemias. Translocation t(6;11)(q24.1;p15.5) with CCDC28A. The chimeric transcript is an in-frame fusion of NUP98 exon 13 to CCDC28A exon 2. Ectopic expression of NUP98- CCDC28A in mouse promotes the proliferative capacity and self- renewal potential of hematopoietic progenitors and rapidly induced fatal myeloproliferative neoplasms and defects in the differentiation of the erythro-megakaryocytic lineage. {ECO:0000269|PubMed:16028218}.;

Recessive Scores

pRec
0.189

Intolerance Scores

LoFtool
0.00393
RVIS EVS
-1.29
RVIS percentile EVS
5.01

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.912

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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