MAP3K20

protein-coding

mitogen-activated protein kinase kinase kinase 20, the group of Mitogen-activated protein kinase kinase kinases

Gene summary

This gene is a member of the MAPKKK family of signal transduction molecules and encodes a protein with an N-terminal kinase catalytic domain, followed by a leucine zipper motif and a sterile-alpha motif (SAM). This magnesium-binding protein forms homodimers and is located in the cytoplasm. The protein mediates gamma radiation signaling leading to cell cycle arrest and activity of this protein plays a role in cell cycle checkpoint regulation in cells. The protein also has pro-apoptotic activity. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

MANE transcript

NM_016653.3

Inheritance

AR, AD

ClinVar variants

P:13U:155B:127

Top phenotype

Split-foot malformation with mesoaxial polydactyly; Myopathy, centronuclear 6, with fiber-type disproportion

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr2:173,075,435-173,268,015

External References & Databases

Ensembl (ENSG00000091436)

Transcript & Mutation Effects

hg38 • Region Span ~192.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

split-foot malformation-mesoaxial polydactyly syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014816

Submitter: Ambry Genetics

congenital fiber-type disproportion myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009711

Submitter: Orphanet

myopathy, centronuclear, 6, with fiber-type disproportionMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0054695

Submitter: G2P

split-foot malformation-mesoaxial polydactyly syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014816

Submitter: Ambry Genetics

syndromic diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0002254

Submitter: PanelApp Australia

myopathy, centronuclear, 6, with fiber-type disproportionSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054695

Submitter: ClinGen

*MAP3K20* was first reported in relation to autosomal recessive centronuclear myopathy with fiber-type disproportion in 2017 (Vasli et al., PMID 27816943). At least four unique truncating variants identified by exome sequencing have been reported in humans in four consanguineous families (PMIDd: 27816943, 36217027). Evidence supporting this gene-disease relationship includes case-level genetic evidence suggesting loss of *MAP3K20,* as well as expression studies suggesting enhanced protein expression in affected tissues (PMID: 27816943). Additionally, MAP3K ZAKβ was established as a kinase activated upon cellular compression, with a particularly pronounced function in skeletal muscle, where it mediates contraction‐induced activation of p38 and JNK and a knockout mouse model recapitulated disease (PMID: 35899396). ZAKβ knockout zebrafish provided further disease modeling with age-related reduced locomotion (PMID: 37427997). In summary, there is strong evidence supporting the relationship between *MAP3K20* and autosomal recessive centronuclear myopathy. This gene-disease pair was originally evaluated by the CM GCEP on 06/08/2020. It was reevaluated on 10/21/2024. As a result of this reevaluation new genetic (PMID: 36217027) and experimental evidence (PMID: 35899396, PMID: 37427997) was identified increasing the classification from Moderate to Strong (SOP Version 11). Of note, biallelic loss-of-function variants in the kinase domain lead to centronuclear myopathy 6, whereas biallelic variants in the SAM domain, which have been associated with increased kinase activity (Vind et al. 2020), have been associated with limb anomalies and hearing loss. Per lumping and splittling guidelines these were considered distinct disease entities and only centronuclear myopathy 6 is included in this curation.

split hand-foot malformationMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0016576

Submitter: Ambry Genetics

split-foot malformation-mesoaxial polydactyly syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014816

Submitter: G2P

myopathy, centronuclear, 6, with fiber-type disproportionSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054695

Submitter: PanelApp Australia

myopathy, centronuclear, 6, with fiber-type disproportionMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0054695

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Split-foot malformation with mesoaxial polydactyly; Myopathy, centronuclear 6, with fiber-type disproportionAD/AR

Manifestation: Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 26755636; 27816943

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAP3K20 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 408

not specifiedTotal: 27

MAP3K20-related disorderTotal: 12

Split-foot malformation-mesoaxial polydactyly syndromeTotal: 6

Inborn genetic diseasesTotal: 5

Myopathy, centronuclear, 6, with fiber-type disproportionTotal: 4

ZAK-related disordersTotal: 1

Centronuclear myopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016653.3. 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			2 clinvar	107 clinvar	2 clinvar	111
missense	1 clinvar		141 clinvar	11 clinvar	7 clinvar	160
nonsense	5 clinvar	1 clinvar	5 clinvar			11
start loss						0
frameshift	3 clinvar	1 clinvar				4
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	7 clinvar			9
Total	10	3	155	118	9	295

Highest pathogenic variant AF is 0.00008993431

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 78 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016653.3	RefSeq	NP_057737.2	19	MANE Select
ENST00000375213.8	Ensembl	ENSP00000364361.3	19	MANE Select
NM_133646.3	RefSeq	NP_598407.1	11	Standard
ENST00000338983.7	Ensembl	ENSP00000340257.3	11	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
Signaling mediated by p38-gamma and p38-delta

Biological Process

DNA damage checkpoint
activation of MAPKK activity
protein phosphorylation
cytoskeleton organization
cell cycle arrest

Molecular Function

magnesium ion binding
RNA binding
protein serine/threonine kinase activity
MAP kinase kinase kinase activity
protein binding

Cellular Component

nucleus
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000375213
Coding exons: 19
Length: 192576
Individuals with no LoFs: 125685
Homozygous LoFs: 0
Heterozygous LoFs: 63
Defined: 125748
p: 0.000251

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.51	335	422	0.794	0.0000212	5262
Missense (PolyPhen)		111	172.62	0.64303		2201
Synonymous	-0.0154	150	150	1.00	0.00000799	1453
Loss of Function	3.26	21	44.4	0.473	0.00000211	550

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0017	0.0017	notable
Latino/Admixed American	0.00021	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00017	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.00027	0.00026	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Stress-activated component of a protein kinase signal transduction cascade. Regulates the JNK and p38 pathways. Part of a signaling cascade that begins with the activation of the adrenergic receptor ADRA1B and leads to the activation of MAPK14. Pro-apoptotic. Role in regulation of S and G2 cell cycle checkpoint by direct phosphorylation of CHEK2 (PubMed:10924358, PubMed:11836244, PubMed:15342622, PubMed:21224381). Involved in limb development (PubMed:26755636). {ECO:0000269|PubMed:10924358, ECO:0000269|PubMed:11836244, ECO:0000269|PubMed:15342622, ECO:0000269|PubMed:21224381, ECO:0000269|PubMed:26755636}.;
Disease: DISEASE: Myopathy, centronuclear, 6, with fiber-type disproportion (CNM6) [MIM:617760]: A form of centronuclear myopathy, a congenital muscle disorder characterized by progressive muscular weakness and wasting involving mainly limb girdle, trunk, and neck muscles. It may also affect distal muscles. Weakness may be present during childhood or adolescence or may not become evident until the third decade of life. Ptosis is a frequent clinical feature. The most prominent histopathologic features include high frequency of centrally located nuclei in muscle fibers not secondary to regeneration, radial arrangement of sarcoplasmic strands around the central nuclei, and predominance and hypotrophy of type 1 fibers. CNM6 is an autosomal recessive, slowly progressive form with onset in infancy or early childhood. {ECO:0000269|PubMed:27816943}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

RVIS EVS: 0.71
RVIS percentile EVS: 85.82

Essentials

Essential (gene trap): N