MYD88

protein-coding

MYD88 innate immune signal transduction adaptor, the group of TIR domain containing|My-T-BRC complex

Gene summary

This gene encodes a cytosolic adapter protein that plays a central role in the innate and adaptive immune response. This protein functions as an essential signal transducer in the interleukin-1 and Toll-like receptor signaling pathways. These pathways regulate that activation of numerous proinflammatory genes. The encoded protein consists of an N-terminal death domain and a C-terminal Toll-interleukin1 receptor domain. Patients with defects in this gene have an increased susceptibility to pyogenic bacterial infections. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2010]

MANE transcript

NM_002468.5

Inheritance

ClinVar variants

P:7U:79B:62

Top phenotype

Immunodeficiency 68

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr3:38,138,552-38,143,024

External References & Databases

Ensembl (ENSG00000172936)

Transcript & Mutation Effects

hg38 • Region Span ~4.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pyogenic bacterial infections due to MyD88 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012839

Submitter: Labcorp Genetics (formerly Invitae)

pyogenic bacterial infections due to MyD88 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012839

Submitter: PanelApp Australia

pyogenic bacterial infections due to MyD88 deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012839

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Immunodeficiency 68AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals have been reported as being susceptible to severe and recurrent pyogenic bacterial infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial

Refs: 18669862; 21057262; 21734245

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MYD88 variants in ClinVar

8 Conditions Cataloged

Pyogenic bacterial infections due to MyD88 deficiencyTotal: 148

Inborn genetic diseasesTotal: 30

not specifiedTotal: 15

not providedTotal: 11

MYD88-related disorderTotal: 4

Macroglobulinemia, Waldenstrom, somaticTotal: 1

Malignant lymphoma, large B-cell, diffuseTotal: 1

MYD88-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002468.5. 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				55 clinvar	1 clinvar	56
missense	1 clinvar		77 clinvar	4 clinvar	2 clinvar	84
nonsense	1 clinvar	1 clinvar	2 clinvar			4
start loss						0
frameshift	1 clinvar	2 clinvar				3
splice donor/acceptor (+/-2bp)		1 clinvar				1
Total	3	4	79	59	3	148

Highest pathogenic variant AF is 0.0000061592623

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002468.5	RefSeq	NP_002459.3	5	MANE Select
ENST00000650905.2	Ensembl	ENSP00000498360.2	5	MANE Select
NM_001172566.2	RefSeq	NP_001166037.2	3	Standard
NM_001172567.2	RefSeq	NP_001166038.2	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
myd88	Danio rerio	Structure: T cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

myd88

Danio rerio

Structure: T cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pertussis - Homo sapiens (human)
Salmonella infection - Homo sapiens (human)
Legionellosis - Homo sapiens (human)
Influenza A - Homo sapiens (human)
African trypanosomiasis - Homo sapiens (human)

Biological Process

toll-like receptor signaling pathway
MyD88-dependent toll-like receptor signaling pathway
apoptotic process
inflammatory response
signal transduction

Molecular Function

death receptor binding
protein binding
identical protein binding
protein self-association
TIR domain binding

Cellular Component

nucleus
cytoplasm
cytosol
plasma membrane
endosome membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000417037
Coding exons: 5
Length: 4545
Individuals with no LoFs: 125658
Homozygous LoFs: 0
Heterozygous LoFs: 90
Defined: 125748
p: 0.000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.11	143	186	0.770	0.0000105	2029
Missense (PolyPhen)		35	61.937	0.56509		684
Synonymous	-0.556	83	76.8	1.08	0.00000415	673
Loss of Function	2.47	4	14.0	0.286	7.64e-7	143

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00015	0.00012	rare
Latino/Admixed American	0.00036	0.00032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000048	0.000046	rare
European (Non-Finnish)	0.00074	0.00062	rare
South Asian	0.000065	0.000065	rare
Other	0.00060	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response (PubMed:15361868, PubMed:18292575). Acts via IRAK1, IRAK2, IRF7 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:15361868, PubMed:24316379, PubMed:19506249). Increases IL-8 transcription (PubMed:9013863). Involved in IL-18-mediated signaling pathway. Activates IRF1 resulting in its rapid migration into the nucleus to mediate an efficient induction of IFN-beta, NOS2/INOS, and IL12A genes. MyD88-mediated signaling in intestinal epithelial cells is crucial for maintenance of gut homeostasis and controls the expression of the antimicrobial lectin REG3G in the small intestine (By similarity). {ECO:0000250|UniProtKB:P22366, ECO:0000269|PubMed:15361868, ECO:0000269|PubMed:18292575, ECO:0000269|PubMed:19506249, ECO:0000269|PubMed:24316379, ECO:0000269|PubMed:9013863}.;
Disease: DISEASE: MYD88 deficiency (MYD88D) [MIM:612260]: Patients suffer from autosomal recessive, life-threatening, often recurrent pyogenic bacterial infections, including invasive pneumococcal disease, and die between 1 and 11 months of age. Surviving patients are otherwise healthy, with normal resistance to other microbes, and their clinical status improved with age. {ECO:0000269|PubMed:18669862, ECO:0000269|PubMed:19506249, ECO:0000269|PubMed:21057262, ECO:0000269|PubMed:24316379}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in MYD88 are frequently found in many hematological malignancies, such as activated B-cell type diffuse large B-cell lymphoma (ABC-DLBCL), Waldenstroem's macroglobulinemia, cutaneous diffuse large B cell lymphoma (CBCL) and primary central nervous system lymphoma (PCNSL). {ECO:0000269|PubMed:21179087, ECO:0000269|PubMed:22931316}.;

Recessive Scores

pRec: 0.122

Intolerance Scores

LoFtool: 0.267
RVIS EVS: -0.34
RVIS percentile EVS: 30.07

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

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