ISG15

ISG15 ubiquitin like modifier

Basic information

Region (hg38): 1:1001137-1014540

Previous symbols: [ "G1P2" ]

Links

ENSG00000187608 ∙ NCBI:9636 ∙ OMIM:147571 ∙ HGNC:4053 ∙ Uniprot:P05161 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency (Limited), mode of inheritance: AR
• Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency (Strong), mode of inheritance: AR
• Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 38, with basal ganglia calcification	AR	Allergy/Immunology/Infectious	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	Allergy/Immunology/Infectious; Neurologic	22859821; 25307056

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ISG15 gene.

• Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency (119 variants)
• Inborn genetic diseases (11 variants)
• not provided (8 variants)
• not specified (3 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ISG15 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	37	6	44
missense			51	2	2	55
nonsense		1	2			3
start loss						0
frameshift			5			5
inframe indel			2			2
splice donor/acceptor (+/-2bp)	1					1
splice region			1	2		3
non coding				1	2	3
Total	1	1	61	40	10

Variants in ISG15

This is a list of pathogenic ClinVar variants found in the ISG15 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-1013466-T-TA		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency • not specified	Benign (Nov 14, 2023)
1-1013490-C-G		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency • not specified	Benign (Nov 14, 2023)
1-1013541-T-C		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency • not specified	Benign (Nov 02, 2023)
1-1013549-GGCCCACAGCCCACA-G		ISG15-related disorder	Likely benign (Sep 17, 2019)
1-1013581-G-C		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Uncertain significance (Jun 29, 2022)
1-1013855-G-A		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Benign (Jul 14, 2021)
1-1013973-G-T		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Likely benign (Dec 28, 2023)
1-1013978-C-A		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Likely benign (Mar 19, 2022)
1-1013980-G-T		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Likely benign (Nov 04, 2022)
1-1013983-G-A		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Pathogenic/Likely pathogenic (Apr 04, 2024)
1-1013986-C-T		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Likely benign (Jun 24, 2020)
1-1013997-C-A		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Uncertain significance (Dec 09, 2023)
1-1013997-C-T		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency • not specified	Uncertain significance (Aug 02, 2022)
1-1013998-G-A		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Likely benign (Oct 03, 2023)
1-1014011-G-A		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Uncertain significance (Jun 04, 2019)
1-1014012-C-T		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Uncertain significance (Jun 18, 2022)
1-1014013-G-A		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Benign (Jan 22, 2024)
1-1014019-C-T		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Likely benign (Jun 29, 2022)
1-1014021-A-T		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Uncertain significance (Nov 14, 2023)
1-1014042-G-A		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Benign (Jan 06, 2024)
1-1014045-C-T		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Uncertain significance (Sep 09, 2021)
1-1014047-A-G		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Uncertain significance (Jul 29, 2022)
1-1014051-C-T		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Uncertain significance (Mar 08, 2022)
1-1014052-G-A		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Likely benign (Dec 01, 2022)
1-1014053-G-T		Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Uncertain significance (Oct 10, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ISG15	protein_coding	protein_coding	ENST00000379389	2	1118

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.405	0.479	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.0441	117	116	1.01	0.00000809	1057
Missense in Polyphen		31	31.318	0.98985		337
Synonymous	-0.500	63	58.1	1.08	0.00000447	363
Loss of Function	0.974	0	1.11	0.00	4.70e-8	12

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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;Cytokine Signaling in Immune system;DDX58/IFIH1-mediated induction of interferon-alpha/beta;Innate Immune System;Immune System;Negative regulators of DDX58/IFIH1 signaling;Termination of translesion DNA synthesis;Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template;DNA Damage Bypass;Interferon alpha/beta signaling;ISG15 antiviral mechanism;Antiviral mechanism by IFN-stimulated genes;Interferon Signaling (Consensus)

Recessive Scores

• pRec: 0.226

Intolerance Scores

• loftool: 0.501
• rvis_EVS: -0.12
• rvis_percentile_EVS: 45.13

Haploinsufficiency Scores

• pHI: 0.100
• hipred: N
• hipred_score: 0.461
• ghis: 0.510

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.894

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Isg15
• Phenotype: skeleton phenotype

Gene ontology

• Biological process: viral process;modification-dependent protein catabolic process;translesion synthesis;positive regulation of bone mineralization;negative regulation of protein ubiquitination;ISG15-protein conjugation;negative regulation of type I interferon production;regulation of interferon-gamma production;response to type I interferon;defense response to bacterium;negative regulation of viral genome replication;positive regulation of erythrocyte differentiation;defense response to virus;type I interferon signaling pathway
• Cellular component: extracellular region;nucleoplasm;cytosol
• Molecular function: protein binding;protein tag