IGHM
otherimmunoglobulin heavy constant mu, the group of Immunoglobulin heavy locus at 14q32.33
Gene summary
Immunoglobulins (Ig) are the antigen recognition molecules of B cells. An Ig molecule is made up of 2 identical heavy chains and 2 identical light chains (see MIM 147200) joined by disulfide bonds so that each heavy chain is linked to a light chain and the 2 heavy chains are linked together. Each Ig heavy chain has an N-terminal variable (V) region containing the antigen-binding site and a C-terminal constant (C) region, encoded by an individual C region gene, that determines the isotype of the antibody and provides effector or signaling functions. The heavy chain V region is encoded by 1 each of 3 types of genes: V genes (see MIM 147070), joining (J) genes (see MIM 147010), and diversity (D) genes (see MIM 146910). The C region genes are clustered downstream of the V region genes within the heavy chain locus on chromosome 14. The IGHM gene encodes the C region of the mu heavy chain, which defines the IgM isotype. Naive B cells express the transmembrane forms of IgM and IgD (see IGHD; MIM 1471770) on their surface. During an antibody response, activated B cells can switch to the expression of individual downstream heavy chain C region genes by a process of somatic recombination known as isotype switching. In addition, secreted Ig forms that act as antibodies can be produced by alternative RNA processing of the heavy chain C region sequences. Although the membrane forms of all Ig isotypes are monomeric, secreted IgM forms pentamers, and occasionally hexamers, in plasma (summary by Janeway et al., 2005).[supplied by OMIM, Aug 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0020729
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0020729
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0020729
Submitter: ClinGen
IGHM was first reported in relation to autosomal recessive agammaglobulinemia 1 in 1996 (Yel L, et al., 1996, PMID: 8890099). IGHM encodes Igμ, which is part of the pre-B-cell antigen receptor complex, that promotes the generation and expansion of a population of large pre-B cells. Agammaglobulinemia 1 is a primary immunodeficiency characterized by profoundly low or absent serum immunoglobulins and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals are susceptible to recurrent infections. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. The mechanism of disease is homozygous loss of function and at least 20 unique variants have been reported in humans, including nonsense, frameshift, and splicing as well as large deletions. Variants in this gene have been reported in at least 9 probands in 5 publications (PMIDs: 8890099, 26910880, 31696364, 12370281, 17410177), and segregated with disease in four additional family members. Additional evidence is available in the literature but the maximum of 12pt for genetic evidence has been reached. Experimentally, this gene-disease relationship is supported by its role in B cell development (PMID: 24378843), which is altered in patient cells (PMID: 11560957). In summary IGHM is definitively associated with autosomal recessive agammaglobulinemia 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0011096
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Gastrointestinal
Intervention: Allergy/Immunology/Infectious
Rationale: Antiinfectious prophylaxis (including with administration of IVIG) and early and aggressive treatment of infections may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to IGHM variants in ClinVar
No annotated ClinVar phenotypes.
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript . 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 | 0 | |||||
| missense | 0 | |||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 0 | 0 | 0 | 0 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| Ensembl | ENSP00000375001.2 | 4 | Standard | |
| Ensembl | ENSP00000490253.1 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Inflammatory Response Pathway
- Antigen activates B Cell Receptor (BCR) leading to generation of second messengers
- B cell receptor signaling
- Signaling by the B Cell Receptor (BCR)
- Immune System
Biological Process
- adaptive immune response
- phagocytosis, recognition
- phagocytosis, engulfment
- complement activation, classical pathway
- antibacterial humoral response
Molecular Function
- single-stranded DNA binding
- antigen binding
- protein binding
- phosphatidylcholine binding
- immunoglobulin receptor binding
Cellular Component
- extracellular space
- plasma membrane
- external side of plasma membrane
- cell surface
- integral component of membrane
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Constant region of immunoglobulin heavy chains. Immunoglobulins, also known as antibodies, are membrane-bound or secreted glycoproteins produced by B lymphocytes. In the recognition phase of humoral immunity, the membrane-bound immunoglobulins serve as receptors which, upon binding of a specific antigen, trigger the clonal expansion and differentiation of B lymphocytes into immunoglobulins-secreting plasma cells. Secreted immunoglobulins mediate the effector phase of humoral immunity, which results in the elimination of bound antigens (PubMed:22158414, PubMed:20176268). The antigen binding site is formed by the variable domain of one heavy chain, together with that of its associated light chain. Thus, each immunoglobulin has two antigen binding sites with remarkable affinity for a particular antigen. The variable domains are assembled by a process called V-(D)-J rearrangement and can then be subjected to somatic hypermutations which, after exposure to antigen and selection, allow affinity maturation for a particular antigen (PubMed:17576170, PubMed:20176268). IgM antibodies play an important role in primary defense mechanisms. They have been shown to be involved in early recognition of external invaders like bacteria and viruses, cellular waste and modified self, as well as in recognition and elimination of precancerous and cancerous lesions. The membrane-bound form is found in the majority of normal B-cells alongside with IgD. Membrane-bound IgM induces the phosphorylation of CD79A and CD79B by the Src family of protein tyrosine kinases. It may cause death of cells by apoptosis. It is also found in soluble form, which represents about 30% of the total serum immunoglobulins where it is found almost exclusively as a homopentamer. After the antigen binds to the B-cell receptor, the secreted form is secreted in large amounts (PubMed:3137579, PubMed:16895553). {ECO:0000269|PubMed:3137579, ECO:0000303|PubMed:16895553, ECO:0000303|PubMed:17576170, ECO:0000303|PubMed:20176268, ECO:0000303|PubMed:22158414}.;
- Disease
- DISEASE: Agammaglobulinemia 1, autosomal recessive (AGM1) [MIM:601495]: A primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life. {ECO:0000269|PubMed:8890099}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Essentials
- Indispensability pred.
- E
- Indispensability score
- 0.914