MAP3K6

protein-coding

mitogen-activated protein kinase kinase kinase 6, the group of Mitogen-activated protein kinase kinase kinases

Gene summary

This gene encodes a serine/threonine protein kinase that forms a component of protein kinase-mediated signal transduction cascades. The encoded kinase participates in the regulation of vascular endothelial growth factor (VEGF) expression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

MANE transcript

NM_004672.5

Inheritance

ClinVar variants

P:1U:218B:41

Top phenotype

Familial gastric cancer

gnomAD constraint

pLI —, LoF o/e 0.58

Max pathogenic AF

—

Genomic locus

chr1:27,355,184-27,366,961

External References & Databases

Ensembl (ENSG00000142733)

Transcript & Mutation Effects

hg38 • Region Span ~11.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary diffuse gastric adenocarcinomaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007648

Submitter: Orphanet

gastric cancerLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0001056

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Familial gastric cancerAD

Manifestation: Oncologic

Intervention: Oncologic

Rationale: Awareness of the risk of diffuse gastric cancer may allow preventive measures and early diagnosis and treatment

Refs: 25340522

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAP3K6 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 224

MAP3K6-related disorderTotal: 27

not providedTotal: 20

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004672.5. 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			7 clinvar	20 clinvar	2 clinvar	29
missense			202 clinvar	11 clinvar	7 clinvar	220
nonsense			1 clinvar			1
start loss						0
frameshift		1 clinvar	1 clinvar			2
splice donor/acceptor (+/-2bp)			7 clinvar	1 clinvar		8
Total	0	1	218	32	9	260

Highest pathogenic variant AF is 0.000048335343

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004672.5	RefSeq	NP_004663.3	29	MANE Select
ENST00000357582.3	Ensembl	ENSP00000350195.2	29	MANE Select
NM_001297609.2	RefSeq	NP_001284538.1	28	Standard
ENST00000374040.7	Ensembl	ENSP00000363152.2	28	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

MAPK signaling pathway - Homo sapiens (human)
EGF-Core
MAPK Signaling Pathway
Angiopoietin Like Protein 8 Regulatory Pathway
Insulin Signaling

Biological Process

activation of MAPKK activity
protein phosphorylation
signal transduction
activation of JUN kinase activity

Molecular Function

magnesium ion binding
protein kinase activity
MAP kinase kinase kinase activity
ATP binding

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000493901
Coding exons: 29
Length: 11709
Individuals with no LoFs: 124657
Homozygous LoFs: 4
Heterozygous LoFs: 1087
Defined: 125748
p: 0.00435

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.24	651	746	0.872	0.0000478	8159
Missense (PolyPhen)		189	237.01	0.79743		2589
Synonymous	1.99	271	316	0.857	0.0000196	2765
Loss of Function	3.05	36	61.9	0.581	0.00000299	705

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00096	0.00092	rare
Latino/Admixed American	0.0045	0.0044	notable
Ashkenazi Jewish	0.0028	0.0027	notable
East Asian	0.0013	0.0013	notable
Finnish	0.010	0.010	notable
European (Non-Finnish)	0.0051	0.0049	notable
South Asian	0.0027	0.0026	notable
Other	0.0042	0.0041	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of a protein kinase signal transduction cascade. Activates the JNK, but not ERK or p38 kinase pathways. {ECO:0000269|PubMed:17210579, ECO:0000269|PubMed:9875215}.;

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.849
RVIS EVS: 0.37
RVIS percentile EVS: 74.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.976

Gene Damage Prediction

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