MAP3K1

mitogen-activated protein kinase kinase kinase 1, the group of Zinc fingers SWIM-type|Ring finger proteins|Mitogen-activated protein kinase kinase kinases

Basic information

Region (hg38): 5:56815548-56896152

Previous symbols: [ "MEKK1" ]

Links

ENSG00000095015 ∙ NCBI:4214 ∙ OMIM:600982 ∙ HGNC:6848 ∙ Uniprot:Q13233 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 46,XY sex reversal 6 (Definitive), mode of inheritance: AD
• 46,XY sex reversal 6 (Strong), mode of inheritance: AD
• 46,XY complete gonadal dysgenesis (Supportive), mode of inheritance: AD
• 46,XY partial gonadal dysgenesis (Supportive), mode of inheritance: AD
• 46,XY sex reversal 6 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
46,XY sex reversal 6	AD	Genitourinary; Oncologic	Surveillance and surgical treatment of gonadal tumors can reduce morbidity	Endocrine; Genitourinary; Oncologic	12476449; 21129722

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MAP3K1 gene.

• 46,XY sex reversal 6 (137 variants)
• not provided (57 variants)
• Inborn genetic diseases (47 variants)
• not specified (23 variants)
• MAP3K1-related condition (2 variants)
• Anophthalmia-microphthalmia syndrome (1 variants)
• Hearing impairment (1 variants)
• See cases (1 variants)
• Hearing loss (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MAP3K1 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	29	22	52
missense	3	5	79	17	12	116
nonsense						0
start loss						0
frameshift						0
inframe indel			4	2	3	9
splice donor/acceptor (+/-2bp)						0
splice region			1	3	1	5
non coding				7	25	32
Total	3	5	84	55	62

Highest pathogenic variant AF is 0.0000197

Variants in MAP3K1

This is a list of pathogenic ClinVar variants found in the MAP3K1 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-56815575-T-TGGC		46,XY sex reversal 6 • not specified	Benign (Dec 28, 2023)
5-56815575-T-TGGCGGC		46,XY sex reversal 6	Uncertain significance (Aug 17, 2022)
5-56815584-C-T		Inborn genetic diseases	Uncertain significance (Jun 03, 2022)
5-56815586-G-C		46,XY sex reversal 6 • Inborn genetic diseases	Uncertain significance (Dec 17, 2023)
5-56815588-G-A		46,XY sex reversal 6	Benign/Likely benign (Nov 27, 2023)
5-56815605-C-T		Inborn genetic diseases	Uncertain significance (Dec 06, 2023)
5-56815617-C-G		46,XY sex reversal 6 • Inborn genetic diseases	Conflicting classifications of pathogenicity (Aug 23, 2022)
5-56815618-G-A		46,XY sex reversal 6	Benign (Dec 02, 2023)
5-56815625-A-G		Inborn genetic diseases	Likely benign (Apr 07, 2023)
5-56815631-A-G		Inborn genetic diseases	Likely benign (Apr 07, 2023)
5-56815638-C-T		Inborn genetic diseases	Uncertain significance (Sep 30, 2021)
5-56815654-C-T		46,XY sex reversal 6	Benign (Jan 18, 2024)
5-56815656-G-T			Uncertain significance (Dec 27, 2022)
5-56815659-G-A		46,XY sex reversal 6	Uncertain significance (Nov 08, 2018)
5-56815662-C-A		46,XY sex reversal 6	Likely benign (Jul 25, 2022)
5-56815673-A-G		Inborn genetic diseases	Uncertain significance (Apr 07, 2023)
5-56815711-G-A		46,XY sex reversal 6	Likely benign (Dec 31, 2019)
5-56815711-G-T		46,XY sex reversal 6	Uncertain significance (Nov 22, 2022)
5-56815716-G-A		Inborn genetic diseases	Uncertain significance (Sep 22, 2023)
5-56815734-G-A		46,XY sex reversal 6	Uncertain significance (Jul 07, 2022)
5-56815736-G-A		46,XY sex reversal 6	Uncertain significance (Mar 08, 2021)
5-56815738-G-A		46,XY sex reversal 6	Benign (Dec 02, 2023)
5-56815742-T-TGGC		46,XY sex reversal 6	Uncertain significance (Mar 08, 2021)
5-56815758-T-G		Inborn genetic diseases	Uncertain significance (May 22, 2023)
5-56815767-T-G		Inborn genetic diseases	Uncertain significance (Aug 02, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MAP3K1	protein_coding	protein_coding	ENST00000399503	20	80579

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000189	124776	0	17	124793	0.0000681

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.67	609	737	0.826	0.0000385	9760
Missense in Polyphen		120	242.1	0.49566		2950
Synonymous	-1.39	288	259	1.11	0.0000131	3039
Loss of Function	6.44	7	61.5	0.114	0.00000319	819

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000152	0.000152
Ashkenazi Jewish	0.0000994	0.0000993
East Asian	0.00	0.00
Finnish	0.0000465	0.0000464
European (Non-Finnish)	0.0000709	0.0000706
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.000331	0.000330

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Component of a protein kinase signal transduction cascade (PubMed:9808624). Activates the ERK and JNK kinase pathways by phosphorylation of MAP2K1 and MAP2K4 (PubMed:9808624). May phosphorylate the MAPK8/JNK1 kinase (PubMed:17761173). Activates CHUK and IKBKB, the central protein kinases of the NF- kappa-B pathway (PubMed:9808624). {ECO:0000269|PubMed:17761173, ECO:0000269|PubMed:9808624}.
• Disease: DISEASE: 46,XY sex reversal 6 (SRXY6) [MIM:613762]: A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females. {ECO:0000269|PubMed:21129722}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Neurotrophin signaling pathway - Homo sapiens (human);Tight junction - Homo sapiens (human);GnRH signaling pathway - Homo sapiens (human);Ubiquitin mediated proteolysis - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Hepatitis B - Homo sapiens (human);RIG-I-like receptor signaling pathway - Homo sapiens (human);EGFR Inhibitor Pathway, Pharmacodynamics;Tacrolimus/Cyclosporine Pathway, Pharmacodynamics;Intracellular Signalling Through Adenosine Receptor A2b and Adenosine;Intracellular Signalling Through Adenosine Receptor A2a and Adenosine;EGF-Core;TGF-Ncore;IL-1 signaling pathway;TNF alpha Signaling Pathway;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;Apoptosis;Polycystic Kidney Disease Pathway;Structural Pathway of Interleukin 1 (IL-1);Cardiac Hypertrophic Response;Fas Ligand (FasL) pathway and Stress induction of Heat Shock Proteins (HSP) regulation;Apoptotic Signaling Pathway;MAPK Signaling Pathway;Apoptosis Modulation by HSP70;RIG-I-like Receptor Signaling;Angiopoietin Like Protein 8 Regulatory Pathway;BMP Signaling Pathway in Eyelid Development;Oxidative Damage;PDGFR-beta pathway;p38 MAPK Signaling Pathway;MAPK Cascade;EGF-EGFR Signaling Pathway;Insulin Signaling;Interferon type I signaling pathways;DNA Damage Response (only ATM dependent);Serotonin HTR1 Group and FOS Pathway;Toll Like Receptor 7/8 (TLR7/8) Cascade;inhibition of cellular proliferation by gleevec;links between pyk2 and map kinases;human cytomegalovirus and map kinase pathways;egf signaling pathway;p38 mapk signaling pathway;tnfr2 signaling pathway;angiotensin ii mediated activation of jnk pathway via pyk2 dependent signaling;cd40l signaling pathway;hiv-1 nef: negative effector of fas and tnf;signal transduction through il1r;tnf/stress related signaling;nf-kb signaling pathway;t cell receptor signaling pathway;bcr signaling pathway;rac1 cell motility signaling pathway;keratinocyte differentiation;toll-like receptor pathway;mapkinase signaling pathway;map kinase inactivation of smrt corepressor;Toll Like Receptor 9 (TLR9) Cascade;MyD88 cascade initiated on plasma membrane;Toll Like Receptor 10 (TLR10) Cascade;Toll Like Receptor 5 (TLR5) Cascade;Toll-Like Receptors Cascades;TRAF6 mediated NF-kB activation;DDX58/IFIH1-mediated induction of interferon-alpha/beta;FCERI mediated MAPK activation;Fc epsilon receptor (FCERI) signaling;Innate Immune System;Immune System;fas signaling pathway (cd95);ceramide signaling pathway;pdgf signaling pathway;IL-7 signaling;fc epsilon receptor i signaling in mast cells;EGFR1;TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation;role of mal in rho-mediated activation of srf;ErbB1 downstream signaling;MyD88 dependent cascade initiated on endosome;BCR signaling pathway;JAK STAT pathway and regulation;PDGF;EPO signaling;IFN-gamma pathway;TLR ECSIT MEKK1 JNK;TLR ECSIT MEKK1 p38;TNFalpha;Toll Like Receptor 4 (TLR4) Cascade;VEGF;EGF;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;Caspase Cascade in Apoptosis;Osteopontin-mediated events;RAC1 signaling pathway;CD40/CD40L signaling;TRAIL signaling pathway;TNF receptor signaling pathway ;CDC42 signaling events;Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met);Fc-epsilon receptor I signaling in mast cells;Regulation of cytoplasmic and nuclear SMAD2/3 signaling;p38 MAPK signaling pathway;FAS (CD95) signaling pathway;JNK signaling in the CD4+ TCR pathway;Role of Calcineurin-dependent NFAT signaling in lymphocytes;Ceramide signaling pathway (Consensus)

Recessive Scores

• pRec: 0.150

Intolerance Scores

• loftool: 0.288
• rvis_EVS: -1.24
• rvis_percentile_EVS: 5.52

Haploinsufficiency Scores

• pHI: 0.213
• hipred: Y
• hipred_score: 0.704
• ghis: 0.526

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.970

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Map3k1
• Phenotype: integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; hearing/vestibular/ear 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); pigmentation phenotype; neoplasm; 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); skeleton phenotype; immune system phenotype; vision/eye phenotype

Gene ontology

• Biological process: MAPK cascade;activation of MAPKK activity;MyD88-dependent toll-like receptor signaling pathway;protein phosphorylation;signal transduction by protein phosphorylation;stress-activated protein kinase signaling cascade;activation of protein kinase activity;Fc-epsilon receptor signaling pathway;cellular response to mechanical stimulus
• Cellular component: cytoplasm;cytosol
• Molecular function: protein kinase activity;protein serine/threonine kinase activity;MAP kinase kinase kinase activity;protein binding;ATP binding;zinc ion binding;protein kinase binding