PSMF1

protein-coding

proteasome inhibitor subunit 1, the group of Proteasome

Gene summary

The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a protein that inhibits the activation of the proteasome by the 11S and 19S regulators. Alternative transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006814.5

Inheritance

ClinVar variants

P:12U:52B:6

Top phenotype

complex neurodevelopmental disorder with motor features

gnomAD constraint

pLI —, LoF o/e 0.93

Max pathogenic AF

—

Genomic locus

chr20:1,113,240-1,189,415

External References & Databases

Ensembl (ENSG00000125818)

Transcript & Mutation Effects

hg38 • Region Span ~76.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorder with motor featuresSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100516

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PSMF1 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 47

PARKINSON DISEASE 27, AUTOSOMAL RECESSIVE EARLY-ONSETTotal: 7

not providedTotal: 5

ARTHROGRYPOSIS MULTIPLEX CONGENITA 8, NEUROGENIC TYPETotal: 5

NEURODEGENERATION, CHILDHOOD-ONSET, WITH MOVEMENT DISORDERS, COGNITIVE DECLINE, AND BRAIN ABNORMALITIESTotal: 2

Complex neurodevelopmental disorder with motor featuresTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006814.5. 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	1 clinvar	1 clinvar	4
missense	4 clinvar	1 clinvar	50 clinvar	3 clinvar	1 clinvar	59
nonsense	1 clinvar					1
start loss	1 clinvar					1
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)	4 clinvar					4
Total	11	1	52	4	2	70

Highest pathogenic variant AF is 0.000014249462

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 45 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006814.5	RefSeq	NP_006805.2	7	MANE Select
ENST00000335877.11	Ensembl	ENSP00000338039.6	7	MANE Select
NM_001323407.2	RefSeq	NP_001310336.1	6	Standard
NM_001323408.2	RefSeq	NP_001310337.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Proteasome - Homo sapiens (human)
Post-translational protein modification
Metabolism of proteins
UCH proteinases
Neddylation

Biological Process

ubiquitin-dependent protein catabolic process
negative regulation of endopeptidase activity
protein deubiquitination
post-translational protein modification
negative regulation of proteasomal protein catabolic process

Molecular Function

endopeptidase inhibitor activity
protein binding
protein homodimerization activity
protein heterodimerization activity
proteasome binding

Cellular Component

nucleoplasm
endoplasmic reticulum
cytosol
proteasome core complex
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000335877
Coding exons: 7
Length: 66691
Individuals with no LoFs: 125713
Homozygous LoFs: 0
Heterozygous LoFs: 35
Defined: 125748
p: 0.000139

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0597	171	169	1.01	0.00000952	1749
Missense (PolyPhen)		55	56.567	0.97229		562
Synonymous	0.0833	67	67.9	0.987	0.00000373	563
Loss of Function	0.236	12	12.9	0.929	6.35e-7	149

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00049	0.00049	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00012	0.00012	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays an important role in control of proteasome function. Inhibits the hydrolysis of protein and peptide substrates by the 20S proteasome. Also inhibits the activation of the proteasome by the proteasome regulatory proteins PA700 and PA28. {ECO:0000269|PubMed:10764772}.;

Recessive Scores

pRec: 0.0916

Intolerance Scores

LoFtool: 0.905
RVIS EVS: 0.42
RVIS percentile EVS: 77.06

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.219

Gene Damage Prediction

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