MALT1
protein-codingMALT1 paracaspase, the group of Immunoglobulin like domain containing|CBM complex
Gene summary
This gene encodes a caspase-like protease that plays a role in BCL10-induced activation of NF-kappaB. The protein is a component of the CARMA1-BCL10-MALT1 (CBM) signalosome that triggers NF-kappaB signaling and lymphoctye activation following antigen-receptor stimulation. Mutations in this gene result in immunodeficiency 12 (IMD12). This gene has been found to be recurrently rearranged in chromosomal translocations with other genes in mucosa-associated lymphoid tissue lymphomas, including a t(11;18)(q21;q21) translocation with the baculoviral IAP repeat-containing protein 3 (also known as apoptosis inhibitor 2) locus [BIRC3(API2)-MALT1], and a t(14;18)(q32;q21) translocation with the immunoglobulin heavy chain locus (IGH-MALT1). Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, May 2018]
- MLT
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~83.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014197
Submitter: ClinGen
Biallelic MALT1 germline loss of function variants were first identified in two siblings with combined immunodeficiency (CID) in 2013 (PMID: 23727036). Autosomal recessive MALT1 deficiency is associated with a combination of recurrent bacterial, viral, or fungal infections, periodontal disease, enteropathy, dermatitis, and failure to thrive. Immunological defects are variable, but typically include normal total T lymphocyte numbers, impaired B cell development with normal/decreased numbers, and variable eosinophilia. There is impaired T cell mitogen proliferation and reduction in Foxp3+ regulatory CD4 T (Treg) cells as well as T helper 17 (TH17) cells. 11 variants have been reported and are composed of missense, frameshift, splice site and indel variants resulting in the loss of function of MALT1. Evidence supporting this gene-disease relationship includes case-level and experimental data. 7 unique variants from 7 individuals across 6 publications were curated (PMID: 23727036, 27253662, 24332264, 31037583, 32858082, 25627829). Heterozygous carriers have not been shown to have a clinical phenotype. More evidence is available in the literature, but the maximum score for genetic evidence has been reached (12 pts). Experimentally, in vitro studies studying MALT1 function use patient derived cells to support this gene-disease relationship. MALT1 is a paracaspase that regulates antigen receptor signaling pathways in lymphocytes. In response to antigen receptor signaling, -MALT1 serves as a scaffold protein for BCL10 and associates with CARD family proteins to generate the CBM signalosome complex. This CBM complex recruits signaling intermediates that lead to the activation of the NF-kB, c-Jun N-terminal kinase (JNK) and the mechanistic target of rapamycin (mTOR) pathways. The MALT1 protein has been shown to be expressed in T and B lymphocytes and is absent in patients with biallelic MALT1 variants with associated CID (PMID:30692685). In vitro functional data demonstrates altered NF-kB signaling in patient cells with MALT1 variants, with associated changes in downstream activation, proliferation, and cytokine production in lymphocytes (PMID:30692685). Mouse models of MALT1 deficiency or alterations of the protease domain show defects in generation and maintenance of B and T lymphocytes, alterations in Foxp3+ regulatory T cell development and alterations in serum immunoglobulin levels (PMID:14576442, 26405015, 25762782). These phenotypic changes are associated with alteration in NF-kB signaling, replicating those defects seen in patients. In summary, MALT1 is definitively associated with combined immunodeficiency. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID-CID Working Group on 7/21/2022 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0014197
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014197
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014197
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014197
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: Individuals have been described as suffering from primary immunodeficiency including infantile-onset recurrent bacterial and candidal infections, and awareness may allow prophylaxis and early and aggressive treatment of infections
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MALT1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006785.4. 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 | 133 | 1 | 134 | |||
| missense | 2 | 1 | 186 | 8 | 1 | 198 |
| nonsense | 3 | 1 | 1 | 5 | ||
| start loss | 0 | |||||
| frameshift | 8 | 3 | 3 | 14 | ||
| splice donor/acceptor (+/-2bp) | 8 | 9 | 17 | |||
| Total | 13 | 13 | 199 | 141 | 2 | 368 |
Highest pathogenic variant AF is 0.00014156853
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006776.1 | 17 | MANE Select | |
| Ensembl | ENSP00000497997.1 | 17 | MANE Select | |
| RefSeq | NP_776216.1 | 16 | Standard | |
| Ensembl | ENSP00000304161.3 | 16 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- T cell receptor signaling pathway - Homo sapiens (human)
- B cell receptor signaling pathway - Homo sapiens (human)
- C-type lectin receptor signaling pathway - Homo sapiens (human)
- Tuberculosis - Homo sapiens (human)
- NF-kappa B signaling pathway - Homo sapiens (human)
Biological Process
- B-1 B cell differentiation
- stimulatory C-type lectin receptor signaling pathway
- positive regulation of T cell cytokine production
- proteolysis
- defense response
Molecular Function
- protease binding
- cysteine-type endopeptidase activity
- ubiquitin-protein transferase activity
- protein binding
- peptidase activity
Cellular Component
- fibrillar center
- nucleus
- nucleolus
- cytoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000348428
- Coding exons
- 17
- Length
- 78754
- Individuals with no LoFs
- 125727
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 18
- Defined
- 125745
- p
- 0.0000716
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.84 | 229 | 386 | 0.593 | 0.0000185 | 5400 |
| Missense (PolyPhen) | 49 | 155.79 | 0.31453 | 2121 | ||
| Synonymous | 1.35 | 118 | 138 | 0.854 | 0.00000670 | 1549 |
| Loss of Function | 4.94 | 6 | 39.5 | 0.152 | 0.00000203 | 533 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00018 | rare |
| Latino/Admixed American | 0.000059 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000099 | 0.000097 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Enhances BCL10-induced activation of NF-kappa-B. Involved in nuclear export of BCL10. Binds to TRAF6, inducing TRAF6 oligomerization and activation of its ligase activity. Has ubiquitin ligase activity. MALT1-dependent BCL10 cleavage plays an important role in T-cell antigen receptor-induced integrin adhesion. Involved in the induction of T helper 17 cells (Th17) differentiation. Cleaves RC3H1 and ZC3H12A in response to T-cell receptor (TCR) stimulation which releases their cooperatively repressed targets to promote Th17 cell differentiation (By similarity). {ECO:0000250|UniProtKB:Q2TBA3, ECO:0000269|PubMed:11262391, ECO:0000269|PubMed:14695475, ECO:0000269|PubMed:18264101}.;
- Disease
- DISEASE: Note=A chromosomal aberration involving MALT1 is recurrent in low-grade mucosa-associated lymphoid tissue (MALT lymphoma). Translocation t(11;18)(q21;q21) with BIRC2. This translocation is found in approximately 50% of cytogenetically abnormal low-grade MALT lymphoma. {ECO:0000269|PubMed:10339464, ECO:0000269|PubMed:10523859, ECO:0000269|PubMed:10702396, ECO:0000269|PubMed:11090634}.;
Recessive Scores
- pRec
- 0.166
Intolerance Scores
- LoFtool
- 0.492
- RVIS EVS
- -0.14
- RVIS percentile EVS
- 43.77
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.627
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |