USP18

protein-coding

ubiquitin specific peptidase 18, the group of Ubiquitin specific peptidases

Gene summary

The protein encoded by this gene belongs to the ubiquitin-specific proteases (UBP) family of enzymes that cleave ubiquitin from ubiquitinated protein substrates. It is highly expressed in liver and thymus, and is localized to the nucleus. This protein efficiently cleaves only ISG15 (a ubiquitin-like protein) fusions, and deletion of this gene in mice results in a massive increase of ISG15 conjugates in tissues, indicating that this protein is a major ISG15-specific protease. Mice lacking this gene are also hypersensitive to interferon, suggesting a function of this protein in downregulating interferon responses, independent of its isopeptidase activity towards ISG15. [provided by RefSeq, Sep 2011]

MANE transcript

NM_017414.4

Inheritance

ClinVar variants

P:4U:51B:21

Top phenotype

Pseudo-TORCH syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr22:18,149,843-18,177,397

External References & Databases

Ensembl (ENSG00000184979)

Transcript & Mutation Effects

hg38 • Region Span ~27.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pseudo-TORCH syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018828

Submitter: G2P

pseudo-TORCH syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018828

Submitter: Labcorp Genetics (formerly Invitae)

pseudo-TORCH syndrome 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0018828

Submitter: Ambry Genetics

pseudo-TORCH syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018828

Submitter: Illumina

pseudo-TORCH syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018828

Submitter: PanelApp Australia

pseudo-TORCH syndrome 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018828

Submitter: Orphanet

Clinical Genomic Database (CGD)

Pseudo-TORCH syndrome 2AR

Manifestation: Cardiovascular; Gastrointestinal; 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: 12833411; 27325888

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to USP18 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 51

not providedTotal: 18

not specifiedTotal: 6

Pseudo-TORCH syndrome 2Total: 6

USP18-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017414.4. 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			1 clinvar	8 clinvar	2 clinvar	11
missense			49 clinvar	9 clinvar	2 clinvar	60
nonsense	1 clinvar	1 clinvar				2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)		2 clinvar	1 clinvar			3
Total	1	3	51	17	4	76

Highest pathogenic variant AF is 0.000026219355

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017414.4	RefSeq	NP_059110.2	10	MANE Select
ENST00000215794.8	Ensembl	ENSP00000215794.7	10	MANE Select
ENST00000699060.2	Ensembl	ENSP00000514107.1	9	Standard
ENST00000699060.3	Ensembl	ENSP00000514107.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
usp18	Danio rerio	Structure: pharyngeal arch cartilage Quality: malformed abnormal

Gene / Model

Organism

Observed Phenotype

usp18

Danio rerio

Structure: pharyngeal arch cartilage

Quality: malformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cytokine Signaling in Immune system
Post-translational protein modification
Metabolism of proteins
Immune System
Ub-specific processing proteases

Biological Process

ubiquitin-dependent protein catabolic process
protein deubiquitination
regulation of protein stability
regulation of inflammatory response
regulation of type I interferon-mediated signaling pathway

Molecular Function

cysteine-type endopeptidase activity
thiol-dependent ubiquitin-specific protease activity
protein binding
ISG15-specific protease activity
thiol-dependent ubiquitinyl hydrolase activity

Cellular Component

nucleus
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000215794
Coding exons: 10
Length: 27499
Individuals with no LoFs: 125734
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 125748
p: 0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.841	158	191	0.829	0.0000102	2458
Missense (PolyPhen)		41	59.425	0.68995		854
Synonymous	-0.144	78	76.4	1.02	0.00000448	660
Loss of Function	2.41	8	19.5	0.411	9.77e-7	240

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00026	0.00025	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00021	0.00020	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000037	0.000035	rare
South Asian	0.00010	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the regulation of inflammatory response to interferon type 1 (PubMed:27325888). Can efficiently cleave only ISG15 fusions including native ISG15 conjugates linked via isopeptide bonds. Necessary to maintain a critical cellular balance of ISG15-conjugated proteins in both healthy and stressed organisms. {ECO:0000269|PubMed:27325888}.;
Disease: DISEASE: Pseudo-TORCH syndrome 2 (PTORCH2) [MIM:617397]: An autosomal recessive multisystem disorder characterized by antenatal onset of intracranial hemorrhage, calcification, brain malformations, liver dysfunction, and often thrombocytopenia. Affected individuals tend to have respiratory insufficiency and seizures, and die in infancy. The phenotype resembles the sequelae of intrauterine infection, but there is no evidence of an infectious agent. {ECO:0000269|PubMed:27325888}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.519
RVIS EVS: 0.26
RVIS percentile EVS: 70.26

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.921

Gene Damage Prediction

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