KMT2A

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

Basic information

Region (hg38): 11:118436455-118526832

Previous symbols: [ "MLL" ]

Links

ENSG00000118058 ∙ NCBI:4297 ∙ OMIM:159555 ∙ HGNC:7132 ∙ Uniprot:Q03164 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Wiedemann-Steiner syndrome (Definitive), mode of inheritance: AD
• Wiedemann-Steiner syndrome (Supportive), mode of inheritance: AD
• Wiedemann-Steiner syndrome (Definitive), mode of inheritance: AD
• Wiedemann-Steiner syndrome (Strong), mode of inheritance: AD
• Wiedemann-Steiner syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Wiedemann-Steiner syndrome	AD	General	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	Craniofacial; Dermatologic; Musculoskeletal; Neurologic	22795537; 25810209

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KMT2A gene.

• not provided (1887 variants)
• Wiedemann-Steiner syndrome (239 variants)
• Inborn genetic diseases (135 variants)
• not specified (36 variants)
• KMT2A-related condition (20 variants)
• Intellectual disability (11 variants)
• See cases (9 variants)
• Neurodevelopmental disorder (5 variants)
• Autism spectrum disorder (4 variants)
• Kabuki syndrome 1 (2 variants)
• Adrenal cortex carcinoma (1 variants)
• Intellectual disability;Hirsutism (1 variants)
• Autism;Intellectual disability (1 variants)
• intellectual deficiency (1 variants)
• Language disorder (1 variants)
• Rare genetic intellectual disability (1 variants)
• Cornelia de Lange syndrome 1 (1 variants)
• Neurodevelopmental delay;Bilateral ptosis;Atypical behavior (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KMT2A gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			7	422	30	459
missense	11	31	934	80	29	1085
nonsense	81	16	2			99
start loss			1			1
frameshift	144	30	1			175
inframe indel		2	25	3		30
splice donor/acceptor (+/-2bp)	17	12	1			30
splice region		2	22	42	2	68
non coding			1	99	49	149
Total	253	91	972	604	108

Highest pathogenic variant AF is 0.00000702

Variants in KMT2A

This is a list of pathogenic ClinVar variants found in the KMT2A region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
11-118436513-A-T		Wiedemann-Steiner syndrome	Uncertain significance (Mar 03, 2022)
11-118436526-G-C			Uncertain significance (May 06, 2022)
11-118436538-T-G		KMT2A-related disorder	Likely pathogenic (Oct 07, 2022)
11-118436539-C-A		Inborn genetic diseases	Uncertain significance (Jul 08, 2022)
11-118436543-G-A		Wiedemann-Steiner syndrome	Uncertain significance (Apr 07, 2022)
11-118436560-C-T			Likely benign (Jul 19, 2022)
11-118436563-G-GGGC			Uncertain significance (Jan 03, 2024)
11-118436566-C-T			Likely benign (Jan 30, 2024)
11-118436570-G-A			Uncertain significance (Jun 13, 2022)
11-118436575-C-T			Likely benign (Jul 17, 2023)
11-118436575-CG-C		Wiedemann-Steiner syndrome	Likely pathogenic (Mar 23, 2021)
11-118436577-G-C			Uncertain significance (May 24, 2023)
11-118436581-G-A			Likely benign (Nov 11, 2023)
11-118436581-G-C			Likely benign (Aug 10, 2021)
11-118436590-C-A			Likely benign (May 01, 2021)
11-118436594-G-A			Uncertain significance (Jul 12, 2023)
11-118436594-G-T		not specified	Uncertain significance (Oct 03, 2023)
11-118436594-GGGGGCGCCCCGCGGCAACGCGTCCCGGCCCTGCTGCTTCCCCCCGGGCCCCCGGTCGGCGGTGGCGGCCCC-G			Likely pathogenic (Aug 01, 2021)
11-118436597-G-T			Uncertain significance (Aug 14, 2023)
11-118436601-C-G		not specified	Benign/Likely benign (Jan 31, 2024)
11-118436601-C-T			Uncertain significance (Jan 25, 2021)
11-118436605-G-A			Likely benign (Aug 24, 2022)
11-118436606-C-A			Likely benign (Aug 04, 2023)
11-118436615-G-A			Uncertain significance (Oct 28, 2023)
11-118436617-C-T			Likely benign (Jul 01, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KMT2A	protein_coding	protein_coding	ENST00000534358	36	90335

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	5.43e-23	125734	0	13	125747	0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	6.23	1271	2.07e+3	0.615	0.000112	25808
Missense in Polyphen		499	1042	0.47889		12874
Synonymous	2.24	688	767	0.897	0.0000410	8159
Loss of Function	11.4	5	161	0.0311	0.0000103	1919

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000290	0.0000290
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000794	0.0000791
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000328	0.0000327
Other	0.000164	0.000163

dbNSFP

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}.
• Pathway: 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;Gene expression (Transcription);Generic Transcription Pathway;PKMTs methylate histone lysines;RNA Polymerase II Transcription;RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function;Chromatin modifying enzymes;Chromatin organization;RUNX1 regulates transcription of genes involved in differentiation of HSCs;Transcriptional regulation by RUNX1 (Consensus)

Recessive Scores

• pRec: 0.489

Intolerance Scores

• rvis_EVS: -3.35
• rvis_percentile_EVS: 0.41

Haploinsufficiency Scores

• pHI: 0.580
• hipred: Y
• hipred_score: 0.728
• ghis: 0.603

Essentials

• essential_gene_CRISPR: E
• essential_gene_gene_trap: K

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Kmt2a
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; craniofacial phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; skeleton phenotype; renal/urinary system phenotype; hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; neoplasm; embryo phenotype

Zebrafish Information Network

• Gene name: kmt2a
• Affected structure: nucleate erythrocyte
• Phenotype tag: abnormal
• Phenotype quality: absent

Gene ontology

• Biological process: transcription by RNA polymerase II;apoptotic process;positive regulation of transporter activity;circadian regulation of gene expression;embryonic hemopoiesis;histone H4-K16 acetylation;regulation of megakaryocyte differentiation;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;histone H3-K4 methylation;positive regulation of histone H3-K4 methylation;protein-containing complex assembly;regulation of histone H3-K14 acetylation;histone H3-K4 trimethylation;regulation of hematopoietic stem cell differentiation;negative regulation of DNA methylation;regulation of histone H3-K9 acetylation;positive regulation of cellular response to drug
• Cellular component: nucleus;nucleoplasm;cytosol;histone methyltransferase complex;MLL1 complex
• 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;zinc ion binding;histone-lysine N-methyltransferase activity;histone methyltransferase activity (H3-K4 specific);identical protein binding;protein homodimerization activity;transcription regulatory region DNA binding;unmethylated CpG binding;lysine-acetylated histone binding