MAP3K7

mitogen-activated protein kinase kinase kinase 7, the group of Mitogen-activated protein kinase kinase kinases

Basic information

Region (hg38): 6:90513573-90587086

Previous symbols: [ "TAK1" ]

Links

ENSG00000135341 ∙ NCBI:6885 ∙ OMIM:602614 ∙ HGNC:6859 ∙ Uniprot:O43318 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• cardiospondylocarpofacial syndrome (Strong), mode of inheritance: AD
• frontometaphyseal dysplasia 1 (Strong), mode of inheritance: AD
• cardiospondylocarpofacial syndrome (Moderate), mode of inheritance: AD
• frontometaphyseal dysplasia 2 (Moderate), mode of inheritance: AD
• frontometaphyseal dysplasia (Supportive), mode of inheritance: AD
• cardiospondylocarpofacial syndrome (Supportive), mode of inheritance: AD
• frontometaphyseal dysplasia (Strong), mode of inheritance: AD
• frontometaphyseal dysplasia 2 (Strong), mode of inheritance: AD
• cardiospondylocarpofacial syndrome (Strong), mode of inheritance: AD
• frontometaphyseal dysplasia 2 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cardiospondylocarpofacial syndrome	AD	Audiologic/Otolaryngologic; Cardiovascular	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; The condition can involve congenital cardiac anomalies, and awareness may allow early management	Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Dermatologic; Genitourinary; Musculoskeletal; Ophthalmologic	10706363; 12503106; 20186786; 25899317; 27426733; 27426734

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MAP3K7 gene.

• not provided (4 variants)
• Cardiospondylocarpofacial syndrome (3 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MAP3K7 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	34	2	37
missense	3	8	82	7	1	101
nonsense			2			2
start loss						0
frameshift						0
inframe indel	1	2	4			7
splice donor/acceptor (+/-2bp)			2			2
splice region	1		11	11	6	29
non coding			3	29	33	65
Total	4	10	94	70	36

Variants in MAP3K7

This is a list of pathogenic ClinVar variants found in the MAP3K7 region.

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

Position	Type	Phenotype	Significance	ClinVar
6-90516541-A-T		Inborn genetic diseases	Uncertain significance (Sep 22, 2023)
6-90516542-C-T		Inborn genetic diseases	Uncertain significance (Oct 03, 2022)
6-90516566-G-C			Uncertain significance (Nov 16, 2023)
6-90516567-G-A			Benign (Jan 25, 2024)
6-90516582-G-T			Uncertain significance (Nov 01, 2022)
6-90516603-C-T			Likely benign (Apr 09, 2022)
6-90516615-C-T			Likely benign (Jul 18, 2022)
6-90516642-G-A			Likely benign (Jul 15, 2018)
6-90516649-T-A			Uncertain significance (May 18, 2023)
6-90516650-C-T			Uncertain significance (Dec 22, 2021)
6-90516659-C-T		Inborn genetic diseases	Uncertain significance (Feb 26, 2024)
6-90516689-C-T			Likely benign (Aug 29, 2022)
6-90518430-C-CATAAAAA			Likely benign (Sep 28, 2023)
6-90518435-A-C			Likely benign (Oct 06, 2023)
6-90518438-A-T			Likely benign (Nov 14, 2023)
6-90518484-T-C			Uncertain significance (May 05, 2022)
6-90518488-A-G			Likely benign (Sep 14, 2022)
6-90518551-C-T			Likely benign (Jan 01, 2023)
6-90518552-G-A		Frontometaphyseal dysplasia 2	Pathogenic (Sep 10, 2022)
6-90518704-A-G			Benign (Jun 19, 2021)
6-90519244-A-C			Benign (Nov 10, 2023)
6-90519253-T-C			Uncertain significance (Jul 18, 2022)
6-90519263-G-A		MAP3K7-related disorder	Likely benign (Oct 09, 2023)
6-90519297-G-A			Likely benign (Sep 13, 2022)
6-90519313-T-C			Uncertain significance (Jun 03, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MAP3K7	protein_coding	protein_coding	ENST00000369329	17	73473

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000291	125729	0	10	125739	0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.79	195	339	0.574	0.0000182	3972
Missense in Polyphen		36	114.35	0.31482		1337
Synonymous	0.260	109	113	0.969	0.00000583	1113
Loss of Function	5.14	3	36.5	0.0821	0.00000177	441

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.000115	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.0000557	0.0000527
Middle Eastern	0.000115	0.000109
South Asian	0.0000697	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2- induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity. {ECO:0000269|PubMed:10094049, ECO:0000269|PubMed:11460167, ECO:0000269|PubMed:12589052, ECO:0000269|PubMed:16845370, ECO:0000269|PubMed:16893890, ECO:0000269|PubMed:21512573, ECO:0000269|PubMed:8663074, ECO:0000269|PubMed:9079627}.
• Disease: DISEASE: Frontometaphyseal dysplasia 2 (FMD2) [MIM:617137]: A form of frontometaphyseal dysplasia, a progressive sclerosing skeletal dysplasia affecting the long bones and skull. Characteristic features include supraorbital hyperostosis, cranial hyperostosis, undermodeling of the small bones, flared metaphyses, and digital anomalies. Extra-skeletal manifestations include hearing loss, cardiac malformations, and stenosis, particularly of the upper airway and urinary tract. FMD2 inheritance is autosomal dominant. {ECO:0000269|PubMed:27426733}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiospondylocarpofacial syndrome (CSCF) [MIM:157800]: A syndrome characterized by growth retardation, dysmorphic facial features, brachydactyly with carpal-tarsal fusion and extensive posterior cervical vertebral synostosis, cardiac septal defects with valve dysplasia, and deafness with inner ear malformations. CSCF transmission pattern is consistent with autosomal dominant inheritance. {ECO:0000269|PubMed:27426734}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: T cell receptor signaling pathway - Homo sapiens (human);Adherens junction - Homo sapiens (human);Autophagy - animal - Homo sapiens (human);TNF signaling pathway - Homo sapiens (human);AMPK signaling pathway - Homo sapiens (human);Toll-like receptor signaling pathway - Homo sapiens (human);NOD-like receptor signaling pathway - Homo sapiens (human);Fluid shear stress and atherosclerosis - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Leishmaniasis - Homo sapiens (human);IL-17 signaling pathway - Homo sapiens (human);Toxoplasmosis - Homo sapiens (human);Measles - Homo sapiens (human);Osteoclast differentiation - Homo sapiens (human);Wnt signaling pathway - Homo sapiens (human);NF-kappa B signaling pathway - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);RIG-I-like receptor signaling pathway - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);Tacrolimus/Cyclosporine Pathway, Pharmacodynamics;EGF-Core;WNT-Ncore;Regulation of toll-like receptor signaling pathway;IL-1 signaling pathway;Angiogenesis overview;RANKL-RANK (Receptor activator of NFKB (ligand)) Signaling Pathway;TNF related weak inducer of apoptosis (TWEAK) Signaling Pathway;IL17 signaling pathway;B Cell Receptor Signaling Pathway;TNF alpha Signaling Pathway;EBV LMP1 signaling;Structural Pathway of Interleukin 1 (IL-1);Cardiac Hypertrophic Response;NLR Proteins;Fas Ligand (FasL) pathway and Stress induction of Heat Shock Proteins (HSP) regulation;Wnt Signaling Pathway;IL-6 signaling pathway;TGF-beta Signaling Pathway;MAPK Signaling Pathway;T-Cell antigen Receptor (TCR) pathway during Staphylococcus aureus infection;RIG-I-like Receptor Signaling;Angiopoietin Like Protein 8 Regulatory Pathway;Wnt Signaling Pathway and Pluripotency;p38 MAPK Signaling Pathway;Wnt Signaling Pathway;Insulin Signaling;T-Cell antigen Receptor (TCR) Signaling Pathway;DNA Damage Response (only ATM dependent);Toll-like Receptor Signaling Pathway;TLR NFkB;Toll Like Receptor 7/8 (TLR7/8) Cascade;Interleukin-17 signaling;Signaling by WNT;Signal Transduction;Signaling by Interleukins;wnt signaling pathway;signal transduction through il1r;alk in cardiac myocytes;nf-kb signaling pathway;thrombin signaling and protease-activated receptors;nfkb activation by nontypeable hemophilus influenzae;toll-like receptor pathway;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;B cell receptor signaling;Toll-Like Receptors Cascades;Downstream TCR signaling;TCR signaling;NOD1/2 Signaling Pathway;Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways;Post-translational protein modification;Activation of NF-kappaB in B cells;Metabolism of proteins;Signaling by the B Cell Receptor (BCR);Interleukin-1 signaling;CLEC7A (Dectin-1) signaling;C-type lectin receptors (CLRs);Fc epsilon receptor (FCERI) signaling;Innate Immune System;Immune System;Adaptive Immune System;BMP2 signaling TAK1;Downstream signaling events of B Cell Receptor (BCR);BCR;fas signaling pathway (cd95);IL-1 NFkB;IL-1 p38;IL-1 JNK;IL1;TLR p38;IL-7 signaling;IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation;TAK1 activates NFkB by phosphorylation and activation of IKKs complex;JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1;TGF_beta_Receptor;activated TAK1 mediates p38 MAPK activation;TNFR1-induced NFkappaB signaling pathway;BMP receptor signaling;MAP kinase activation;TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation;tgf beta signaling pathway;TNF signaling;Ca2+ pathway;Beta-catenin independent WNT signaling;MyD88 dependent cascade initiated on endosome;Ub-specific processing proteases;BCR signaling pathway;JAK STAT pathway and regulation;Noncanonical Wnt signaling pathway;Deubiquitination;EPO signaling;Death Receptor Signalling;C-MYB transcription factor network;Ephrin B reverse signaling;TGF-beta signaling TAK1;FCERI mediated NF-kB activation;IL6;Wnt;TNFalpha;TLR JNK;TRAF6-mediated induction of TAK1 complex within TLR4 complex;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade;VEGF;IRAK2 mediated activation of TAK1 complex;MyD88:Mal cascade initiated on plasma membrane;Toll Like Receptor TLR1:TLR2 Cascade;RANKL;Toll Like Receptor TLR6:TLR2 Cascade;Toll Like Receptor 2 (TLR2) Cascade;TNF receptor signaling pathway ;p38 MAPK signaling pathway;JNK signaling in the CD4+ TCR pathway;IL1-mediated signaling events;Presenilin action in Notch and Wnt signaling;TGF-beta receptor signaling;Interleukin-1 family signaling;CD4 T cell receptor signaling-NFkB cascade;TICAM1,TRAF6-dependent induction of TAK1 complex;CD4 T cell receptor signaling (Consensus)

Recessive Scores

• pRec: 0.338

Intolerance Scores

• loftool: 0.0769
• rvis_EVS: -0.43
• rvis_percentile_EVS: 25.15

Haploinsufficiency Scores

• pHI: 0.800
• hipred: Y
• hipred_score: 0.825
• ghis: 0.716

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Map3k7
• Phenotype: vision/eye phenotype; digestive/alimentary phenotype; limbs/digits/tail 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); skeleton phenotype; immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; embryo phenotype; neoplasm; growth/size/body region 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); hematopoietic system phenotype; 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); craniofacial phenotype; muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype

Gene ontology

• Biological process: activation of MAPKK activity;activation of MAPK activity;stimulatory C-type lectin receptor signaling pathway;positive regulation of T cell cytokine production;MyD88-dependent toll-like receptor signaling pathway;transforming growth factor beta receptor signaling pathway;Wnt signaling pathway, calcium modulating pathway;I-kappaB kinase/NF-kappaB signaling;activation of NF-kappaB-inducing kinase activity;I-kappaB phosphorylation;JNK cascade;viral process;positive regulation of macroautophagy;protein deubiquitination;positive regulation of interleukin-2 production;Fc-epsilon receptor signaling pathway;positive regulation of I-kappaB kinase/NF-kappaB signaling;anoikis;positive regulation of JUN kinase activity;histone H3 acetylation;T cell receptor signaling pathway;positive regulation of NF-kappaB transcription factor activity;stress-activated MAPK cascade;nucleotide-binding oligomerization domain containing signaling pathway;interleukin-1-mediated signaling pathway
• Cellular component: nucleus;Ada2/Gcn5/Ada3 transcription activator complex;cytosol;plasma membrane;IkappaB kinase complex;endosome membrane
• Molecular function: magnesium ion binding;protein kinase activity;protein serine/threonine kinase activity;MAP kinase kinase kinase activity;protein binding;ATP binding;receptor tyrosine kinase binding;identical protein binding;scaffold protein binding