GeneBe

KMT2A

protein-coding

lysine methyltransferase 2A, the group of PHD finger proteins|SET domain containing|Zinc fingers CXXC-type|Lysine methyltransferases|Bromodomain containing

Gene summary

This gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, the SET domain, is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation. This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C and MLL-N. These fragments reassociate and further assemble into different multiprotein complexes that regulate the transcription of specific target genes, including many of the HOX genes. Multiple chromosomal translocations involving this gene are the cause of certain acute lymphoid leukemias and acute myeloid leukemias. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2010]

Previous symbols:
  • MLL

MANE transcript

NM_001197104.2

Inheritance

AD

ClinVar variants

P:592U:1804B:1117

Top phenotype

Wiedemann-Steiner syndrome

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chr11:118,436,456-118,526,832

External References & Databases

Ensembl (ENSG00000118058)NCBI Gene (4297)OMIM (159555)HGNC:7132GenCCUniProt (Q03164)AlphaFoldClinVar (KMT2A)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~90.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Wiedemann-Steiner syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011518

Submitter: G2P

Wiedemann-Steiner syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011518

Submitter: Orphanet

Wiedemann-Steiner syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011518

Submitter: Illumina

Wiedemann-Steiner syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011518

Submitter: ClinGen

The KMT2A gene is located on chromosome 11 at 11q23.3 and encodes the lysine methyltransferase 2A with histone H3 lysine 4 (H3K4) methyltransferase activity. KMT2A was first reported in relation to autosomal dominant Wiedemann-Steiner syndrome in 2000 (Steiner et al., PMID: 10826636). Characteristic features for this disorder include mild to profound intellectual disability, musculoskeletal anomalies, distinctive facial features, hypertrichosis cubiti, short stature, and behavioral issues. Additional features include alterations of the corpus callosum, growth restriction, failure to thrive, feeding difficulties, cardiac anomalies, micrognathia, high arched palate, and dental anomalies. At least 8 unique variants (including frameshift, stop-gained, and missense variants) have been reported in 8 probands in 4 publications (Jones et al., 2012, PMID: 22795537; Miyake et al., 2016, PMID: 25810209; Baer et al., 2018, PMID: 29574747; Lebrun et al., 2018, PMID: 29203834) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be de novo loss of function variants but de novo missense variants have also been reported. This disorder presents with a widely variable phenotype. This gene-disease association is also supported by mouse models and expression studies (Yu et al., 1995, PMID: 7477409; Ayton et al., 2001, PMID: 11536426, Wang et al., 2009, PMID: 19703992). In summary, KMT2A is definitively associated with autosomal dominant Wiedemann-Steiner syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 02.23.2022 (SOP Version 8).

Wiedemann-Steiner syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011518

Submitter: Labcorp Genetics (formerly Invitae)

Wiedemann-Steiner syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011518

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Wiedemann-Steiner syndromeAD

Manifestation: Craniofacial; Dermatologic; Musculoskeletal; Neurologic

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: 22795537; 25810209Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KMT2A variants in ClinVar

23 Conditions Cataloged
not providedTotal: 3245
Wiedemann-Steiner syndromeTotal: 464
Inborn genetic diseasesTotal: 401
not specifiedTotal: 276
KMT2A-related disorderTotal: 209
Intellectual disabilityTotal: 22
See casesTotal: 11
Neurodevelopmental disorderTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001197104.2. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
12
clinvar
819
clinvar
17
clinvar
 849
missense
15
clinvar
56
clinvar
1767
clinvar
261
clinvar
17
clinvar
 2116
nonsense
113
clinvar
46
clinvar
4
clinvar
1
clinvar
 164
start loss
1
clinvar
 1
frameshift
228
clinvar
84
clinvar
11
clinvar
2
clinvar
 325
splice donor/acceptor (+/-2bp)
24
clinvar
25
clinvar
9
clinvar
 58
Total38021218041080373513

Highest pathogenic variant AF is 0.00010177814

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001197104.2RefSeqNP_001184033.136MANE Select
ENST00000534358.8EnsemblENSP00000436786.236MANE Select
NM_001412597.1RefSeqNP_001399526.137Standard
NM_005933.4RefSeqNP_005924.236Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
kmt2aDanio rerio

Structure: nucleate erythrocyte

Quality: absent

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Cushing,s syndrome - Homo sapiens (human)
  • Lysine degradation - Homo sapiens (human)
  • Transcriptional misregulation in cancer - Homo sapiens (human)
  • Histone Modifications
  • Senescence and Autophagy in Cancer

Biological Process

  • transcription by RNA polymerase II
  • apoptotic process
  • positive regulation of transporter activity
  • circadian regulation of gene expression
  • embryonic hemopoiesis

Molecular Function

  • RNA polymerase II distal enhancer sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • AT DNA binding
  • DNA-binding transcription factor activity
  • protein binding

Cellular Component

  • nucleus
  • nucleoplasm
  • cytosol
  • histone methyltransferase complex
  • MLL1 complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000534358
Coding exons
36
Length
90335
Individuals with no LoFs
125734
Homozygous LoFs
0
Heterozygous LoFs
13
Defined
125747
p
0.0000517
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense6.2312712.07e+30.6150.00011225808
Missense (PolyPhen)49910420.4788912874
Synonymous2.246887670.8970.00004108159
Loss of Function11.451610.03110.00001031919

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish00.0absent
European (Non-Finnish)0.0000790.000079rare
South Asian0.0000330.000033rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Histone methyltransferase that plays an essential role in early development and hematopoiesis. Catalytic subunit of the MLL1/MLL complex, a multiprotein complex that mediates both methylation of 'Lys-4' of histone H3 (H3K4me) complex and acetylation of 'Lys-16' of histone H4 (H4K16ac). In the MLL1/MLL complex, it specifically mediates H3K4me, a specific tag for epigenetic transcriptional activation (PubMed:12453419, PubMed:20677832, PubMed:26886794). Has weak methyltransferase activity by itself, and requires other component of the MLL1/MLL complex to obtain full methyltransferase activity (PubMed:19187761, PubMed:26886794). Has no activity toward histone H3 phosphorylated on 'Thr-3', less activity toward H3 dimethylated on 'Arg-8' or 'Lys-9', while it has higher activity toward H3 acetylated on 'Lys-9'. Binds to unmethylated CpG elements in the promoter of target genes and helps maintain them in the nonmethylated state (PubMed:20010842). Required for transcriptional activation of HOXA9 (PubMed:12453419, PubMed:20677832, PubMed:20010842). Promotes PPP1R15A-induced apoptosis. Plays a critical role in the control of circadian gene expression and is essential for the transcriptional activation mediated by the CLOCK-ARNTL/BMAL1 heterodimer. Establishes a permissive chromatin state for circadian transcription by mediating a rhythmic methylation of 'Lys-4' of histone H3 (H3K4me) and this histone modification directs the circadian acetylation at H3K9 and H3K14 allowing the recruitment of CLOCK-ARNTL/BMAL1 to chromatin (By similarity). {ECO:0000250|UniProtKB:P55200, ECO:0000269|PubMed:10490642, ECO:0000269|PubMed:12453419, ECO:0000269|PubMed:15960975, ECO:0000269|PubMed:19187761, ECO:0000269|PubMed:19556245, ECO:0000269|PubMed:20010842, ECO:0000269|PubMed:26886794, ECO:0000305|PubMed:20677832}.;
Disease
DISEASE: Wiedemann-Steiner syndrome (WDSTS) [MIM:605130]: A syndrome characterized by hairy elbows (hypertrichosis cubiti), intellectual disability, a distinctive facial appearance, and short stature. Facial characteristics include long eyelashes, thick or arched eyebrows with a lateral flare, and downslanting and vertically narrow palpebral fissures. {ECO:0000269|PubMed:22795537}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Chromosomal aberrations involving KMT2A are a cause of acute leukemias. Translocation t(1;11)(q21;q23) with MLLT11/AF1Q; translocation t(3;11)(p21;q23) with NCKIPSD/AF3p21; translocation t(3,11)(q25,q23) with GMPS; translocation t(4;11)(q21;q23) with AFF1/MLLT2/AF4; insertion ins(5;11)(q31;q13q23) with AFF4/AF5Q31; translocation t(5;11)(q12;q23) with AF5-alpha/CENPK; translocation t(6;11)(q27;q23) with AFDN; translocation t(9;11)(p22;q23) with MLLT3/AF9; translocation t(10;11)(p11.2;q23) with ABI1; translocation t(10;11)(p12;q23) with MLLT10/AF10; t(11;15)(q23;q14) with KNL1 and ZFYVE19; translocation t(11;17)(q23;q21) with MLLT6/AF17; translocation t(11;19)(q23;p13.3) with ELL; translocation t(11;19)(q23;p13.3) with MLLT1/ENL; translocation t(11;19)(q23;p23) with GAS7; translocation t(X;11)(q13;q23) with FOXO4/AFX1. Translocation t(3;11)(q28;q23) with LPP. Translocation t(10;11)(q22;q23) with TET1. Translocation t(9;11)(q34;q23) with DAB2IP. Translocation t(4;11)(p12;q23) with FRYL. Fusion proteins KMT2A-MLLT1, KMT2A- MLLT3 and KMT2A-ELL interact with PPP1R15A and, on the contrary to unfused KMT2A, inhibit PPP1R15A-induced apoptosis. {ECO:0000269|PubMed:10490642}.; DISEASE: Note=A chromosomal aberration involving KMT2A may be a cause of chronic neutrophilic leukemia. Translocation t(4;11)(q21;q23) with SEPT11. {ECO:0000269|PubMed:10490642}.;

Recessive Scores

pRec
0.489

Intolerance Scores

RVIS EVS
-3.35
RVIS percentile EVS
0.41

Essentials

Essential (CRISPR)
E
Essential (gene trap)
K

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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