IGHM

immunoglobulin heavy constant mu, the group of Immunoglobulin heavy locus at 14q32.33

Basic information

Region (hg38): 14:105851704-105856218

Links

ENSG00000211899 ∙ NCBI:3507 ∙ OMIM:147020 ∙ HGNC:5541 ∙ Uniprot:P01871 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal agammaglobulinemia (Supportive), mode of inheritance: AD
• autosomal recessive agammaglobulinemia 1 (Strong), mode of inheritance: AR
• autosomal recessive agammaglobulinemia 1 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Agammaglobulinemia 1	AR	Allergy/Immunology/Infectious	Antiinfectious prophylaxis (including with administration of IVIG) and early and aggressive treatment of infections may be beneficial	Allergy/Immunology/Infectious; Gastrointestinal	8890099; 12370281; 21039741

ClinVar

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

• Autosomal recessive agammaglobulinemia 1 (12 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the IGHM 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				3	4
missense	2				1	3
nonsense	1	1				2
start loss						0
frameshift	1	1				2
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding				1		1
Total	5	2	0	1	4

Highest pathogenic variant AF is 0.0000200

Variants in IGHM

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

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

Position	Type	Phenotype	Significance	ClinVar
14-105851916-A-T		not specified	Benign (Jan 24, 2024)
14-105852010-C-T		not specified	Benign (Jan 24, 2024)
14-105852108-C-T		not specified	Benign (Jan 24, 2024)
14-105854405-C-T		Autosomal recessive agammaglobulinemia 1	Pathogenic (Oct 01, 2002)
14-105854468-A-C		Autosomal recessive agammaglobulinemia 1	Pathogenic (Oct 01, 2002)
14-105854900-G-T		Autosomal recessive agammaglobulinemia 1	Likely benign (Apr 11, 2019)
14-105855041-A-G		Autosomal recessive agammaglobulinemia 1	Benign (Sep 13, 2022)
14-105855107-C-T		Autosomal recessive agammaglobulinemia 1	Pathogenic (Oct 01, 2002)
14-105855130-A-AG		Autosomal recessive agammaglobulinemia 1	Likely pathogenic (-)
14-105855203-G-A		Autosomal recessive agammaglobulinemia 1	Benign (Sep 13, 2022)
14-105855558-C-T		not specified	Benign (Jan 24, 2024)
14-105855621-CTT-C		Autosomal recessive agammaglobulinemia 1	Pathogenic (Oct 01, 2002)
14-105855808-A-G		not specified	Benign (Jan 24, 2024)
14-105855988-G-C		Autosomal recessive agammaglobulinemia 1	Benign (Sep 25, 2018)
14-105856013-G-T		Autosomal recessive agammaglobulinemia 1	Likely pathogenic (Dec 28, 2021)
14-105856087-G-A		Autosomal recessive agammaglobulinemia 1	Pathogenic (Apr 15, 2016)
14-105856156-C-T		Autosomal recessive agammaglobulinemia 1	Benign (Jan 01, 2023)

GnomAD

Source: gnomAD

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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;Adaptive Immune System;CD22 mediated BCR regulation;BCR;Cell surface interactions at the vascular wall;Hemostasis (Consensus)

Haploinsufficiency Scores

• ghis: 0.499

Essentials

• gene_indispensability_pred: E
• gene_indispensability_score: 0.914

Gene ontology

• Biological process: adaptive immune response;phagocytosis, recognition;phagocytosis, engulfment;complement activation, classical pathway;antibacterial humoral response;defense response to bacterium;innate immune response;defense response to Gram-negative bacterium;B cell receptor signaling pathway;positive regulation of B cell activation;leukocyte migration
• Cellular component: extracellular space;plasma membrane;external side of plasma membrane;cell surface;integral component of membrane;immunoglobulin complex, circulating;extracellular exosome;pentameric IgM immunoglobulin complex;hexameric IgM immunoglobulin complex;blood microparticle
• Molecular function: single-stranded DNA binding;antigen binding;protein binding;phosphatidylcholine binding;immunoglobulin receptor binding;peptidoglycan binding