ITCH
itchy E3 ubiquitin protein ligase, the group of HECT domain containing|C2 domain containing|MicroRNA protein coding host genes
Basic information
Region (hg38): 20:34363235-34511773
Links
Phenotypes
GenCC
Source:
- syndromic multisystem autoimmune disease due to ITCH deficiency (Strong), mode of inheritance: AR
- syndromic multisystem autoimmune disease due to ITCH deficiency (Moderate), mode of inheritance: AR
- syndromic multisystem autoimmune disease due to ITCH deficiency (Supportive), mode of inheritance: AR
- syndromic multisystem autoimmune disease due to ITCH deficiency (Strong), mode of inheritance: AR
- syndromic multisystem autoimmune disease due to ITCH deficiency (Definitive), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Autoimmune disease, syndromic multisystem, with facial dysmorphism | AR | Allergy/Immunology/Infectious; Endocrine | Individuals typically present with multisystem malformations, which may aid in clinical recognition, but awareness of disease may allow corticosteroid and other related immunosuppressive treatment related to autoimmune manifestations (including hypothyroidism, which responds to standard hormone replacement therapy), as well as awareness of the risk of frequent infections, which can allow prophylaxis/surveillance for infectious diseases, and early and aggressive treatment of infections | Allergy/Immunology/Infectious; Craniofacial; Endocrine; Gastrointestinal; Neurologic; Pulmonary | 20170897 |
ClinVar
This is a list of variants' phenotypes submitted to
- Syndromic_multisystem_autoimmune_disease_due_to_ITCH_deficiency (423 variants)
- Inborn_genetic_diseases (55 variants)
- not_provided (25 variants)
- ITCH-related_disorder (15 variants)
- not_specified (3 variants)
- See_cases (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the ITCH gene is commonly pathogenic or not. These statistics are base on transcript: NM_000031483.7. Only rare variants are included in the table.
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.
| Effect | PathogenicP | Likely pathogenicLP | VUSVUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 124 | 131 | ||||
| missense | 170 | 176 | ||||
| nonsense | 7 | |||||
| start loss | 1 | 1 | ||||
| frameshift | 6 | |||||
| splice donor/acceptor (+/-2bp) | 3 | |||||
| Total | 11 | 3 | 176 | 130 | 4 |
Highest pathogenic variant AF is 0.00000342284
Loading clinvar variants...
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| ITCH | protein_coding | protein_coding | ENST00000262650 | 24 | 148158 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 1.00 | 0.0000290 | 125737 | 0 | 9 | 125746 | 0.0000358 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 3.58 | 263 | 485 | 0.542 | 0.0000252 | 5924 |
| Missense in Polyphen | 59 | 183.3 | 0.32187 | 2145 | ||
| Synonymous | -1.03 | 181 | 164 | 1.10 | 0.00000824 | 1654 |
| Loss of Function | 6.36 | 7 | 60.3 | 0.116 | 0.00000325 | 681 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.0000578 | 0.0000578 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.00 | 0.00 |
| Finnish | 0.000231 | 0.000139 |
| European (Non-Finnish) | 0.0000266 | 0.0000264 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.0000327 | 0.0000327 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Acts as an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates (PubMed:14602072, PubMed:17028573, PubMed:16387660, PubMed:18718448, PubMed:18718449, PubMed:11046148, PubMed:19592251, PubMed:19116316, PubMed:19881509, PubMed:20491914, PubMed:20392206, PubMed:20068034, PubMed:23146885, PubMed:24790097, PubMed:25631046). Catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation (PubMed:17028573, PubMed:18718448, PubMed:19131965, PubMed:19881509). Involved in the control of inflammatory signaling pathways (PubMed:19131965). Essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways (PubMed:19131965). Promotes the association of the complex after TNF stimulation (PubMed:19131965). Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains (PubMed:19131965). This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1 (PubMed:19131965). Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways (PubMed:19592251). Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response (PubMed:18718448, PubMed:20491914). Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages (PubMed:18718448). Mediates JUN ubiquitination and degradation (By similarity). Mediates JUNB ubiquitination and degradation (PubMed:16387660). Critical regulator of type 2 helper T (Th2) cell cytokine production by inducing JUNB ubiquitination and degradation (By similarity). Involved in the negative regulation of MAVS-dependent cellular antiviral responses (PubMed:19881509). Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation (PubMed:19881509). Following ligand stimulation, regulates sorting of Wnt receptor FZD4 to the degradative endocytic pathway probably by modulating PI42KA activity (PubMed:23146885). Ubiquitinates PI4K2A and negatively regulates its catalytic activity (PubMed:23146885). Ubiquitinates chemokine receptor CXCR4 and regulates sorting of CXCR4 to the degradative endocytic pathway following ligand stimulation by ubiquitinating endosomal sorting complex required for transport ESCRT-0 components HGS and STAM (PubMed:14602072, PubMed:23146885). Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination (PubMed:17028573, PubMed:18628966, PubMed:23886940). Ubiquitinates SNX9 (PubMed:20491914). Ubiquitinates MAP3K7 through 'Lys-48'- linked conjugation (By similarity). Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP (PubMed:20068034). Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID (PubMed:20392206). Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046). {ECO:0000250|UniProtKB:Q8C863, ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:16387660, ECO:0000269|PubMed:17028573, ECO:0000269|PubMed:18628966, ECO:0000269|PubMed:18718448, ECO:0000269|PubMed:18718449, ECO:0000269|PubMed:19116316, ECO:0000269|PubMed:19131965, ECO:0000269|PubMed:19592251, ECO:0000269|PubMed:19881509, ECO:0000269|PubMed:20068034, ECO:0000269|PubMed:20392206, ECO:0000269|PubMed:20491914, ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:23886940, ECO:0000269|PubMed:24790097, ECO:0000269|PubMed:25631046}.;
- Disease
- DISEASE: Autoimmune disease, multisystem, with facial dysmorphism (ADMFD) [MIM:613385]: A disorder characterized by organomegaly, failure to thrive, developmental delay, dysmorphic features and autoimmune inflammatory cell infiltration of the lungs, liver and gut. {ECO:0000269|PubMed:20170897}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human);Endocytosis - Homo sapiens (human);Ubiquitin mediated proteolysis - Homo sapiens (human);TNF signaling pathway - Homo sapiens (human);TGF-Ncore;TGF-beta Signaling Pathway;VEGFA-VEGFR2 Signaling Pathway;Transcriptional regulation by RUNX1;EGF-EGFR Signaling Pathway;Notch Signaling Pathway;Notch;Signal Transduction;Gene expression (Transcription);Generic Transcription Pathway;NOD1/2 Signaling Pathway;Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways;DDX58/IFIH1-mediated induction of interferon-alpha/beta;RNA Polymerase II Transcription;Notch;Innate Immune System;Immune System;Adaptive Immune System;p73 transcription factor network;Signaling by NOTCH1;Antigen processing: Ubiquitination & Proteasome degradation;Downregulation of ERBB4 signaling;Class I MHC mediated antigen processing & presentation;Signaling by NOTCH;ErbB4 signaling events;Degradation of GLI1 by the proteasome;Hedgehog ,off, state;Hedgehog ,on, state;Signaling by Hedgehog;EGFR1;CXCR4-mediated signaling events;Negative regulators of DDX58/IFIH1 signaling;Validated transcriptional targets of TAp63 isoforms;Notch signaling pathway;RUNX1 regulates transcription of genes involved in differentiation of HSCs;Signaling by ERBB4;TNFalpha;TNF;Signaling by Receptor Tyrosine Kinases;Transcriptional regulation by RUNX1;Calcineurin-regulated NFAT-dependent transcription in lymphocytes;Validated transcriptional targets of deltaNp63 isoforms;Activated NOTCH1 Transmits Signal to the Nucleus
(Consensus)
Recessive Scores
- pRec
- 0.0847
Intolerance Scores
- loftool
- 0.194
- rvis_EVS
- -1.09
- rvis_percentile_EVS
- 7.05
Haploinsufficiency Scores
- pHI
- 0.594
- hipred
- Y
- hipred_score
- 0.707
- ghis
- 0.600
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.871
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Itch
- Phenotype
- homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); skeleton phenotype; immune system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); respiratory system phenotype;
Zebrafish Information Network
- Gene name
- itchb
- Affected structure
- posterior lateral line primordium
- Phenotype tag
- abnormal
- Phenotype quality
- disorganized
Gene ontology
- Biological process
- protein polyubiquitination;regulation of cell growth;positive regulation of T cell anergy;ubiquitin-dependent protein catabolic process;apoptotic process;inflammatory response;Notch signaling pathway;protein ubiquitination;negative regulation of NF-kappaB transcription factor activity;negative regulation of type I interferon production;protein K29-linked ubiquitination;negative regulation of apoptotic process;proteasome-mediated ubiquitin-dependent protein catabolic process;innate immune response;positive regulation of protein catabolic process;negative regulation of JNK cascade;negative regulation of alpha-beta T cell proliferation;viral entry into host cell;negative regulation of defense response to virus;defense response to virus;protein autoubiquitination;nucleotide-binding oligomerization domain containing signaling pathway;protein K63-linked ubiquitination;protein K48-linked ubiquitination;regulation of protein deubiquitination;regulation of hematopoietic stem cell differentiation;positive regulation of receptor catabolic process
- Cellular component
- nucleoplasm;cytoplasm;early endosome;cytosol;plasma membrane;cell cortex;membrane;early endosome membrane;protein-containing complex;intracellular membrane-bounded organelle;extracellular exosome
- Molecular function
- ubiquitin-protein transferase activity;protein binding;ligase activity;ubiquitin-like protein transferase activity;ribonucleoprotein complex binding;ubiquitin-like protein ligase binding;CXCR chemokine receptor binding;ubiquitin protein ligase activity;arrestin family protein binding