PSMC1

protein-coding

proteasome 26S subunit, ATPase 1, the group of Proteasome|AAA ATPases

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 one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. This subunit and a 20S core alpha subunit interact specifically with the hepatitis B virus X protein, a protein critical to viral replication. This subunit also interacts with the adenovirus E1A protein and this interaction alters the activity of the proteasome. Finally, this subunit interacts with ataxin-7, suggesting a role for the proteasome in the development of spinocerebellar ataxia type 7, a progressive neurodegenerative disorder. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002802.3

Inheritance

AR, AD

ClinVar variants

P:1U:13B:2

Top phenotype

Birk-Aharoni syndrome (Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss)

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr14:90,256,527-90,275,429

External References & Databases

Ensembl (ENSG00000100764)

Transcript & Mutation Effects

hg38 • Region Span ~18.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing lossLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859296

Submitter: Ambry Genetics

neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing lossLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859296

Submitter: PanelApp Australia

neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing lossLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0859296

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

Clinical Genomic Database (CGD)

Birk-Aharoni syndrome (Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss)AR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Endocrine; Genitourinary; Hematologic; Musculoskeletal; Neurologic

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: 35861243

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PSMC1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 10

not providedTotal: 4

Prostate cancerTotal: 1

Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing lossTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002802.3. 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		2
missense	1 clinvar		13 clinvar			14
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	1	0	13	2	0	16

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002802.3	RefSeq	NP_002793.2	11	MANE Select
ENST00000261303.13	Ensembl	ENSP00000261303.8	11	MANE Select
NM_001330212.2	RefSeq	NP_001317141.1	8	Standard
ENST00000543772.2	Ensembl	ENSP00000445147.2	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Viral carcinogenesis - Homo sapiens (human)
Epstein-Barr virus infection - Homo sapiens (human)
Proteasome - Homo sapiens (human)
Human papillomavirus infection - Homo sapiens (human)
Proteasome Degradation

Biological Process

protein folding
protein deubiquitination
protein catabolic process
post-translational protein modification
negative regulation of neuron death

Molecular Function

RNA binding
protein binding
ATP binding
ATPase activity
TBP-class protein binding

Cellular Component

proteasome complex
nucleus
nucleoplasm
cytosol
proteasome regulatory particle, base subcomplex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261303
Coding exons: 11
Length: 16130
Individuals with no LoFs: 125709
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125713
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.95	66	237	0.278	0.0000123	2885
Missense (PolyPhen)		10	58.65	0.1705		756
Synonymous	0.350	83	87.2	0.952	0.00000479	838
Loss of Function	4.31	0	21.6	0.00	0.00000117	284

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000036	0.000026	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC1 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides. {ECO:0000269|PubMed:1317798}.;

Intolerance Scores

LoFtool: 0.280
RVIS EVS: -0.3
RVIS percentile EVS: 32.62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.801

Gene Damage Prediction

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