GeneBe

ISG15

protein-coding

ISG15 ubiquitin like modifier

Gene summary

The protein encoded by this gene is a ubiquitin-like protein that is conjugated to intracellular target proteins upon activation by interferon-alpha and interferon-beta. Several functions have been ascribed to the encoded protein, including chemotactic activity towards neutrophils, direction of ligated target proteins to intermediate filaments, cell-to-cell signaling, and antiviral activity during viral infections. While conjugates of this protein have been found to be noncovalently attached to intermediate filaments, this protein is sometimes secreted. [provided by RefSeq, Dec 2012]

Previous symbols:
  • G1P2

MANE transcript

NM_005101.4

Inheritance

AR

ClinVar variants

P:5U:70B:63

Top phenotype

Immunodeficiency 38, with basal ganglia calcification

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr1:1,001,138-1,014,540

External References & Databases

Ensembl (ENSG00000187608)NCBI Gene (9636)OMIM (147571)HGNC:4053GenCCUniProt (P05161)AlphaFoldClinVar (ISG15)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~13.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014502

Submitter: Ambry Genetics

Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014502

Submitter: Labcorp Genetics (formerly Invitae)

Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014502

Submitter: PanelApp Australia

Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014502

Submitter: Orphanet

Clinical Genomic Database (CGD)

Immunodeficiency 38, with basal ganglia calcificationAR

Manifestation: Allergy/Immunology/Infectious; Neurologic

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals may sufffer from severe infections (including Mycobacterial and Salmonella), and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; BCG vaccine has been reported as resulting in adverse reactions

Refs: 22859821; 25307056Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ISG15 variants in ClinVar

4 Conditions Cataloged
Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiencyTotal: 139
not specifiedTotal: 41
not providedTotal: 21
ISG15-related disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005101.4. 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.

EffectPLPVUSLBBSum
synonymous
55
clinvar
 55
missense
1
clinvar
63
clinvar
8
clinvar
 72
nonsense
1
clinvar
1
clinvar
2
clinvar
 4
start loss
0
frameshift
1
clinvar
5
clinvar
 6
splice donor/acceptor (+/-2bp)
1
clinvar
 1
Total2370630138

Highest pathogenic variant AF is 0.000011634703

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_005101.4RefSeqNP_005092.12MANE Select
ENST00000649529.1EnsemblENSP00000496832.12MANE Select
ENST00000624652.1EnsemblENSP00000485313.11Standard
ENST00000624697.4EnsemblENSP00000485643.11Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • RIG-I-like receptor signaling pathway - Homo sapiens (human)
  • Human papillomavirus infection - Homo sapiens (human)
  • RIG-I-like Receptor Signaling
  • Type II interferon signaling (IFNG)
  • DNA Repair

Biological Process

  • viral process
  • modification-dependent protein catabolic process
  • translesion synthesis
  • positive regulation of bone mineralization
  • negative regulation of protein ubiquitination

Molecular Function

  • protein binding
  • protein tag

Cellular Component

  • extracellular region
  • nucleoplasm
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000379389
Coding exons
2
Length
1118
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.04411171161.010.000008091057
Missense (PolyPhen)3131.3180.98985337
Synonymous-0.5006358.11.080.00000447363
Loss of Function0.97401.110.004.70e-812

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein. ISGylation involves a cascade of enzymatic reactions involving E1, E2, and E3 enzymes which catalyze the conjugation of ISG15 to a lysine residue in the target protein. Its target proteins include IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B and CHMP6. Can also isgylate: EIF2AK2/PKR which results in its activation, DDX58/RIG-I which inhibits its function in antiviral signaling response, EIF4E2 which enhances its cap structure-binding activity and translation- inhibition activity, UBE2N and UBE2E1 which negatively regulates their activity, IRF3 which inhibits its ubiquitination and degradation and FLNB which prevents its ability to interact with the upstream activators of the JNK cascade therby inhibiting IFNA- induced JNK signaling. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A, HIV-1 and Ebola virus. Restricts HIV-1 and ebola virus via disruption of viral budding. Inhibits the ubiquitination of HIV-1 Gag and host TSG101 and disrupts their interaction, thereby preventing assembly and release of virions from infected cells. Inhibits Ebola virus budding mediated by the VP40 protein by disrupting ubiquitin ligase activity of NEDD4 and its ability to ubiquitinate VP40. ISGylates influenza A virus NS1 protein which causes a loss of function of the protein and the inhibition of virus replication. The secreted form of ISG15 can: induce natural killer cell proliferation, act as a chemotactic factor for neutrophils and act as a IFN-gamma-inducing cytokine playing an essential role in antimycobacterial immunity. {ECO:0000269|PubMed:1373138, ECO:0000269|PubMed:16009940, ECO:0000269|PubMed:16112642, ECO:0000269|PubMed:16428300, ECO:0000269|PubMed:16434471, ECO:0000269|PubMed:16872604, ECO:0000269|PubMed:18305167, ECO:0000269|PubMed:19270716, ECO:0000269|PubMed:19357168, ECO:0000269|PubMed:2005397, ECO:0000269|PubMed:20133869, ECO:0000269|PubMed:20308324, ECO:0000269|PubMed:20639253, ECO:0000269|PubMed:21543490, ECO:0000269|PubMed:22693631, ECO:0000269|PubMed:22859821, ECO:0000269|PubMed:23229543, ECO:0000269|PubMed:7526157, ECO:0000269|PubMed:8550581}.;
Disease
DISEASE: Immunodeficiency 38, with basal ganglia calcification (IMD38) [MIM:616126]: A primary immunodeficiency predisposing individuals to severe clinical disease upon infection with weakly virulent mycobacteria, including Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccines. Patients are also susceptible to Salmonella and Mycobacterium tubercolosis infections. Affected individuals have intracranial calcification. {ECO:0000269|PubMed:22859821}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.226

Intolerance Scores

LoFtool
0.501
RVIS EVS
-0.12
RVIS percentile EVS
45.13

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.894

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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