MAP3K8

mitogen-activated protein kinase kinase kinase 8, the group of Mitogen-activated protein kinase kinase kinases

Basic information

Region (hg38): 10:30434021-30461833

Previous symbols: [ "COT", "ESTF" ]

Links

ENSG00000107968 ∙ NCBI:1326 ∙ OMIM:191195 ∙ HGNC:6860 ∙ Uniprot:P41279 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MAP3K8 gene.

• not_provided (191 variants)
• not_specified (25 variants)
• MAP3K8-related_disorder (13 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MAP3K8 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000005204.4. 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	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	63	7	72
missense			101	1	1	103
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	103	64	8

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MAP3K8	protein_coding	protein_coding	ENST00000263056	7	27897

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.968	0.0317	125743	0	4	125747	0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.29	165	271	0.608	0.0000152	3070
Missense in Polyphen		39	102.02	0.38229		1083
Synonymous	-1.23	117	101	1.16	0.00000589	901
Loss of Function	3.67	2	19.5	0.103	0.00000101	242

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000617	0.0000615
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.00	0.00
Finnish	0.0000463	0.0000462
European (Non-Finnish)	0.00000894	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Required for lipopolysaccharide (LPS)-induced, TLR4- mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the proinflammatory cytokine TNF- alpha (TNF) during immune responses. Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. In vitro, activates MAPK/ERK pathway in response to IL1 in an IRAK1-independent manner, leading to up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals that activate ERK in B- cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle. Isoform 1 shows some transforming activity, although it is much weaker than that of the activated oncogenic variant. {ECO:0000269|PubMed:11342626, ECO:0000269|PubMed:12667451, ECO:0000269|PubMed:15169888, ECO:0000269|PubMed:16371247, ECO:0000269|PubMed:1833717, ECO:0000269|PubMed:19001140, ECO:0000269|PubMed:19754427, ECO:0000269|PubMed:19808894}.
• Pathway: T cell receptor signaling pathway - Homo sapiens (human);TNF signaling pathway - Homo sapiens (human);Toll-like receptor signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);EGF-Core;Regulation of toll-like receptor signaling pathway;miR-targeted genes in epithelium - TarBase;miR-targeted genes in leukocytes - TarBase;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in squamous cell - TarBase;TNF alpha Signaling Pathway;Structural Pathway of Interleukin 1 (IL-1);MAPK Signaling Pathway;T-Cell antigen Receptor (TCR) pathway during Staphylococcus aureus infection;Angiopoietin Like Protein 8 Regulatory Pathway;Insulin Signaling;T-Cell antigen Receptor (TCR) Signaling Pathway;Toll-like Receptor Signaling Pathway;Toll Like Receptor 7/8 (TLR7/8) Cascade;Interleukin-17 signaling;Signaling by Interleukins;mapkinase signaling pathway;Cytokine Signaling in Immune system;Toll Like Receptor 9 (TLR9) Cascade;MyD88 cascade initiated on plasma membrane;Toll Like Receptor 10 (TLR10) Cascade;Toll Like Receptor 3 (TLR3) Cascade;Toll Like Receptor 5 (TLR5) Cascade;Toll-Like Receptors Cascades;CD28 dependent PI3K/Akt signaling;CD28 co-stimulation;Costimulation by the CD28 family;Interleukin-1 signaling;Innate Immune System;Immune System;Adaptive Immune System;IL-7 signaling;MAP3K8 (TPL2)-dependent MAPK1/3 activation;MAP kinase activation;TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation;Ras signaling in the CD4+ TCR pathway;MyD88 dependent cascade initiated on endosome;JAK STAT pathway and regulation;EPO signaling;TNFalpha;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade;VEGF;MyD88:Mal cascade initiated on plasma membrane;Toll Like Receptor TLR1:TLR2 Cascade;Toll Like Receptor TLR6:TLR2 Cascade;Toll Like Receptor 2 (TLR2) Cascade;TCR signaling in naïve CD8+ T cells;JNK signaling in the CD4+ TCR pathway;Role of Calcineurin-dependent NFAT signaling in lymphocytes;TCR signaling in naïve CD4+ T cells;Interleukin-1 family signaling (Consensus)

Recessive Scores

• pRec: 0.267

Intolerance Scores

• loftool: 0.234
• rvis_EVS: -0.89
• rvis_percentile_EVS: 10.3

Haploinsufficiency Scores

• pHI: 0.232
• hipred: Y
• hipred_score: 0.775
• ghis: 0.597

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.998

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Map3k8
• Phenotype: growth/size/body region phenotype; homeostasis/metabolism phenotype; cellular phenotype; hematopoietic 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); 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); neoplasm; immune system phenotype; digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Gene ontology

• Biological process: activation of MAPKK activity;protein phosphorylation;cell cycle;signal transduction by protein phosphorylation;stress-activated protein kinase signaling cascade;T cell costimulation;activation of protein kinase activity;stress-activated MAPK cascade;interleukin-1-mediated signaling pathway
• Cellular component: cytoplasm;cytosol
• Molecular function: magnesium ion binding;protein serine/threonine kinase activity;MAP kinase kinase kinase activity;protein binding;ATP binding