NUP93

protein-coding

nucleoporin 93, 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. This gene encodes a nucleoporin protein that localizes both to the basket of the pore and to the nuclear entry of the central gated channel of the pore. The encoded protein is a target of caspase cysteine proteases that play a central role in programmed cell death by apoptosis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]

MANE transcript

NM_014669.5

Inheritance

AR, AD

ClinVar variants

P:21U:144B:77

Top phenotype

Nephrotic syndrome, type 12

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr16:56,730,118-56,850,286

External References & Databases

Ensembl (ENSG00000102900)

Transcript & Mutation Effects

hg38 • Region Span ~120.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nephrotic syndrome, type 12STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014817

Submitter: Labcorp Genetics (formerly Invitae)

nephrotic syndrome, type 12STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014817

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

nephrotic syndrome, type 12DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014817

Submitter: ClinGen

The relationship between NUP93 (or Nuclear Pore Complex Protein 93) and AR Nephrotic syndrome type 12 was evaluated using the ClinGen Clinical Validity Framework. The NUP93 gene encodes a protein that regulates the flow of proteins between the nucleus and the cytoplasm. It also regulates the podocyte migration and proliferation through Smad4 signalling. It is expressed ubiquitously including in the kidney cortex and medulla, and in podocytes and in the developing kidney. NUP93 was first reported in relation to nephrotic syndrome by Braun in 2016 (PMID: 26878725). This is the only disease associated with pathogenic variants in this gene. The clinical presentation is with the development of the nephrotic syndrome at years 1- 6 and kidney failure a few years later. Pathogenic variants include truncating variants, splice site variants and missense changes that are associated with human disease. The mechanism of pathogenicity is Loss of Function. The gene-disease association is supported by experimental expression, protein interaction data, functional alterations in non-patient cells and in non-human model organisms and with rescue experiments in cell lines. In summary, NUP93 is definitively associated with AR nephrotic syndrome. This has been demonstrated in both the clinical diagnostic and research setting, and has been upheld over time. This assessment was performed according to the ClinGen Gene Clinical Validity SOP version 9 and was approved by the Glomerulopathy Working Group on 26 July 2022.

familial idiopathic steroid-resistant nephrotic syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019006

Submitter: Orphanet

nephrotic syndrome, type 12MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014817

Submitter: Ambry Genetics

nephrotic syndrome, type 12STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014817

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Nephrotic syndrome, type 12AR

Manifestation: Renal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 26878725

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NUP93 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 176

Inborn genetic diseasesTotal: 94

NUP93-related disorderTotal: 40

Nephrotic syndrome, type 12Total: 38

not specifiedTotal: 20

Nephrotic syndromeTotal: 5

Focal segmental glomerulosclerosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014669.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	60 clinvar	6 clinvar	68
missense		7 clinvar	138 clinvar	10 clinvar	1 clinvar	156
nonsense	1 clinvar	2 clinvar	3 clinvar			6
start loss						0
frameshift	3 clinvar	3 clinvar				6
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	1 clinvar			6
Total	6	15	144	70	7	242

Highest pathogenic variant AF is 0.0005799012

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 91 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014669.5	RefSeq	NP_055484.3	21	MANE Select
ENST00000308159.10	Ensembl	ENSP00000310668.5	21	MANE Select
NM_001242795.2	RefSeq	NP_001229724.1	18	Standard
NM_001242796.2	RefSeq	NP_001229725.1	18	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
nup93	Danio rerio	Structure: head Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

nup93

Danio rerio

Structure: head

Quality: decreased size

abnormal

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
nuclear envelope organization
viral process
poly(A)+ mRNA export from nucleus

Molecular Function

protein binding
structural constituent of nuclear pore

Cellular Component

nuclear envelope
nuclear pore
membrane
nuclear membrane
nuclear periphery

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000308159
Coding exons: 21
Length: 114781
Individuals with no LoFs: 125712
Homozygous LoFs: 0
Heterozygous LoFs: 36
Defined: 125748
p: 0.000143

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.30	409	490	0.835	0.0000298	5375
Missense (PolyPhen)		115	151.7	0.7581		1763
Synonymous	-0.934	208	192	1.09	0.0000119	1575
Loss of Function	4.05	19	49.9	0.381	0.00000289	527

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00055	0.00049	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000060	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance (PubMed:9348540). May anchor nucleoporins, but not NUP153 and TPR, to the NPC. During renal development, regulates podocyte migration and proliferation through SMAD4 signaling (PubMed:26878725). {ECO:0000269|PubMed:15229283, ECO:0000269|PubMed:15703211, ECO:0000269|PubMed:26878725, ECO:0000269|PubMed:9348540}.;
Disease: DISEASE: Nephrotic syndrome 12 (NPHS12) [MIM:616892]: A form of nephrotic syndrome, a renal disease clinically characterized by severe proteinuria, resulting in complications such as hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation. Some affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure. NPHS12 inheritance is autosomal recessive. {ECO:0000269|PubMed:26878725}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.102

Intolerance Scores

LoFtool: 0.678
RVIS EVS: -1.41
RVIS percentile EVS: 4.13

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.969

Gene Damage Prediction

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