MAP3K3

protein-coding

mitogen-activated protein kinase kinase kinase 3, the group of Mitogen-activated protein kinase kinase kinases

Gene summary

This gene product is a 626-amino acid polypeptide that is 96.5% identical to mouse Mekk3. Its catalytic domain is closely related to those of several other kinases, including mouse Mekk2, tobacco NPK, and yeast Ste11. Northern blot analysis revealed a 4.6-kb transcript that appears to be ubiquitously expressed. This protein directly regulates the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by activating SEK and MEK1/2 respectively; it does not regulate the p38 pathway. In cotransfection assays, it enhanced transcription from a nuclear factor kappa-B (NFKB)-dependent reporter gene, consistent with a role in the SAPK pathway. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

Previous symbols:

MEKK3

MANE transcript

NM_002401.5

Inheritance

ClinVar variants

P:1U:95B:7

Top phenotype

cerebral cavernous malformations 5

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chr17:63,622,415-63,696,305

External References & Databases

Ensembl (ENSG00000198909)

Transcript & Mutation Effects

hg38 • Region Span ~73.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cerebral cavernous malformations 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0975952

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAP3K3 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 86

not providedTotal: 11

Cerebral cavernous malformations 5Total: 8

MAP3K3-related disorderTotal: 3

Verrucous hemangiomaTotal: 2

MAP3K3-Related DiseaseTotal: 1

CEREBRAL CAVERNOUS MALFORMATIONS 5, SOMATICTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002401.5. 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			3 clinvar	2 clinvar	3 clinvar	8
missense		1 clinvar	88 clinvar	1 clinvar	1 clinvar	91
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	1	95	3	4	103

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 51 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002401.5	RefSeq	NP_002392.2	16	MANE Select
ENST00000361733.8	Ensembl	ENSP00000354485.4	16	MANE Select
NM_001330431.2	RefSeq	NP_001317360.1	16	Standard
NM_001363768.2	RefSeq	NP_001350697.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neurotrophin signaling pathway - Homo sapiens (human)
GnRH signaling pathway - Homo sapiens (human)
HTLV-I infection - Homo sapiens (human)
MAPK signaling pathway - Homo sapiens (human)
EGF-Core

Biological Process

MAPK cascade
activation of MAPKK activity
blood vessel development
signal transduction by protein phosphorylation
stress-activated protein kinase signaling cascade

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: ENST00000361357
Coding exons: 17
Length: 73889
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125748
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.04	293	409	0.716	0.0000256	4326
Missense (PolyPhen)		67	138	0.48552		1373
Synonymous	0.797	137	149	0.917	0.00000874	1261
Loss of Function	4.92	6	39.3	0.153	0.00000233	415

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of a protein kinase signal transduction cascade. Mediates activation of the NF-kappa-B, AP1 and DDIT3 transcriptional regulators. {ECO:0000269|PubMed:12912994, ECO:0000269|PubMed:14661019, ECO:0000269|PubMed:14743216, ECO:0000269|PubMed:9006902}.;

Recessive Scores

pRec: 0.240

Intolerance Scores

LoFtool: 0.183
RVIS EVS: -1.07
RVIS percentile EVS: 7.37

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.997

Gene Damage Prediction

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