MAP3K1

protein-coding

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

Gene summary

The protein encoded by this gene is a serine/threonine kinase and is part of some signal transduction cascades, including the ERK and JNK kinase pathways as well as the NF-kappa-B pathway. The encoded protein is activated by autophosphorylation and requires magnesium as a cofactor in phosphorylating other proteins. This protein has E3 ligase activity conferred by a plant homeodomain (PHD) in its N-terminus and phospho-kinase activity conferred by a kinase domain in its C-terminus. [provided by RefSeq, Mar 2012]

Previous symbols:

MEKK1

MANE transcript

NM_005921.2

Inheritance

ClinVar variants

P:16U:268B:127

Top phenotype

46,XY sex reversal 6

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr5:56,815,549-56,896,152

External References & Databases

Ensembl (ENSG00000095015)

Transcript & Mutation Effects

hg38 • Region Span ~80.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

46,XY partial gonadal dysgenesisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016674

Submitter: Orphanet

46,XY sex reversal 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013410

Submitter: Labcorp Genetics (formerly Invitae)

breast cancerMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007254

Submitter: G2P

46,XY sex reversal 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013410

Submitter: PanelApp Australia

46,XY sex reversal 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013410

Submitter: Ambry Genetics

46,XY complete gonadal dysgenesisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010765

Submitter: Orphanet

46,XY sex reversal 6DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013410

Submitter: G2P

Clinical Genomic Database (CGD)

46,XY sex reversal 6AD

Manifestation: Endocrine; Genitourinary; Oncologic

Intervention: Genitourinary; Oncologic

Rationale: Surveillance and surgical treatment of gonadal tumors can reduce morbidity

Refs: 12476449; 21129722

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAP3K1 variants in ClinVar

13 Conditions Cataloged

46,XY sex reversal 6Total: 204

Inborn genetic diseasesTotal: 176

not providedTotal: 48

not specifiedTotal: 48

MAP3K1-related disorderTotal: 32

Ovarian neoplasmTotal: 5

Disorder of sexual differentiationTotal: 2

Anophthalmia-microphthalmia syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005921.2. 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			7 clinvar	63 clinvar	16 clinvar	86
missense	5 clinvar	6 clinvar	245 clinvar	43 clinvar	5 clinvar	304
nonsense	1 clinvar		2 clinvar			3
start loss						0
frameshift	3 clinvar		2 clinvar			5
splice donor/acceptor (+/-2bp)		1 clinvar	12 clinvar			13
Total	9	7	268	106	21	411

Highest pathogenic variant AF is 0.0000647448

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005921.2	RefSeq	NP_005912.1	20	MANE Select
ENST00000399503.4	Ensembl	ENSP00000382423.3	20	MANE Select
ENST00000872824.1	Ensembl	ENSP00000542883.1	19	Standard
ENST00000872824.2	Ensembl	ENSP00000542883.1	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

Biological Process

MAPK cascade
activation of MAPKK activity
MyD88-dependent toll-like receptor signaling pathway
protein phosphorylation
signal transduction by protein phosphorylation

Molecular Function

protein kinase activity
protein serine/threonine kinase activity
MAP kinase kinase kinase activity
protein binding
ATP binding

Cellular Component

cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000399503
Coding exons: 20
Length: 80579
Individuals with no LoFs: 124776
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 124793
p: 0.0000681

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.67	609	737	0.826	0.0000385	9760
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000071	0.000071	rare
South Asian	0.000033	0.000033	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.150

Intolerance Scores

LoFtool: 0.288
RVIS EVS: -1.24
RVIS percentile EVS: 5.52

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.970

Gene Damage Prediction

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