NUP50

protein-coding

nucleoporin 50, the group of Nucleoporins

Gene summary

The nuclear pore complex is a massive structure that extends across the nuclear envelope, forming a gateway that regulates the flow of macromolecules between the nucleus and the cytoplasm. Nucleoporins are the main components of the nuclear pore complex in eukaryotic cells. The protein encoded by this gene is a member of the FG-repeat containing nucleoporins that functions as a soluble cofactor in importin-alpha:beta-mediated nuclear protein import. Pseudogenes of this gene are found on chromosomes 5, 6, and 14. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

NPAP60L

MANE transcript

NM_007172.4

Inheritance

ClinVar variants

U:75B:2

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr22:45,163,925-45,188,017

External References & Databases

Ensembl (ENSG00000093000)

Transcript & Mutation Effects

hg38 • Region Span ~24.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

amyotrophic lateral sclerosisLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: ClinGen

Variants in the NUP50 gene have been not been reported with disease previously. The NUP50 gene encodes nuclear pore glycoprotein p50, a nuclear pore complex component. The nuclear pore complex spans the nuclear envelope and allows the flow of molecules (proteins, RNA, carbohydrates, lipids and signaling molecules) between the nucleus and cytoplasm. Nuclear pore dysfunction precedes TDP-43 mislocalisation in neurons of sporadic ALS patients, and reciprocally is exacerbated by TDP-43 and FUS aggregation. A case-control rare variant burden analysis of whole-genome sequencing data identified a burden of 11 damaging variants in NUP50 among FTD/ALS cases compared to controls (PMID: 36670122). Loss-of-function variants in the NUP50 gene have been reported till date in individuals with FTD/ALS (PMIDs: 36670122). In all instances of literature when available, affected probands with NUP50 variants are identified to have dysregulation of protein expression levels (PMIDs: 36670122). There is in vivo data suggesting that deletion of NUP50 gene affects the motor phenotype. The maximum score for genetic evidence through aggregate variant analysis is 3 (Limited 0-6) being reported in the paper by Megat et al (PMID: 36670122).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NUP50 variants in ClinVar

1 Conditions Cataloged

not specifiedTotal: 73

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007172.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous						0
missense			74 clinvar	2 clinvar		76
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	75	2	0	77

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007172.4	RefSeq	NP_009103.2	7	MANE Select
ENST00000347635.9	Ensembl	ENSP00000345895.3	7	MANE Select
NM_153645.2	RefSeq	NP_705931.1	6	Standard
ENST00000396096.6	Ensembl	ENSP00000379403.2	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

RNA transport - Homo sapiens (human)
tRNA processing
Disease
Gene expression (Transcription)
Regulation of HSF1-mediated heat shock response

Biological Process

mRNA export from nucleus
protein import into nucleus
viral process
positive regulation of GTPase activity

Molecular Function

GTPase activator activity
protein binding
Ran GTPase binding

Cellular Component

nucleus
nuclear pore
nucleoplasm
cytoplasm
nuclear membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000347635
Coding exons: 7
Length: 24175
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125748
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0728	263	260	1.01	0.0000139	3071
Missense (PolyPhen)		51	78.675	0.64823		966
Synonymous	-1.59	121	101	1.20	0.00000598	912
Loss of Function	2.88	4	16.7	0.239	7.81e-7	238

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the nuclear pore complex that has a direct role in nuclear protein import (PubMed:20016008). Actively displaces NLSs from importin-alpha, and facilitates disassembly of the importin-alpha:beta-cargo complex and importin recycling (PubMed:20016008). Interacts with regulatory proteins of cell cycle progression including CDKN1B (By similarity). This interaction is required for correct intracellular transport and degradation of CDKN1B (By similarity). {ECO:0000250|UniProtKB:Q9JIH2, ECO:0000269|PubMed:20016008}.;

Recessive Scores

pRec: 0.120

Intolerance Scores

LoFtool: 0.247
RVIS EVS: -0.76
RVIS percentile EVS: 13.33

Essentials

Essential (CRISPR): N
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.602

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium