KDM6A

lysine demethylase 6A, the group of Lysine demethylases|Tetratricopeptide repeat domain containing

Basic information

Region (hg38): X:44873188-45112779

Previous symbols: [ "UTX" ]

Links

ENSG00000147050 ∙ NCBI:7403 ∙ OMIM:300128 ∙ HGNC:12637 ∙ Uniprot:O15550 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Kabuki syndrome 2 (Definitive), mode of inheritance: XLD
• Kabuki syndrome 2 (Strong), mode of inheritance: XL
• Kabuki syndrome 2 (Strong), mode of inheritance: XL
• Kabuki syndrome (Supportive), mode of inheritance: AD
• Kabuki syndrome 2 (Definitive), mode of inheritance: XL
• Kabuki syndrome 2 (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Kabuki syndrome 2	XL	Cardiovascular	The condition can involve congenital cardiac anomalies, and awareness may allow early management	Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic	22197486; 23076834; 24633898

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KDM6A gene.

• Kabuki syndrome 2 (46 variants)
• not provided (24 variants)
• Inborn genetic diseases (4 variants)
• Malignant tumor of urinary bladder (2 variants)
• Kabuki syndrome 1 (1 variants)
• Kabuki syndrome 1;Kabuki syndrome 2 (1 variants)
• KDM6A-related disorder (1 variants)
• Neurodevelopmental disorder (1 variants)
• Autism spectrum disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KDM6A 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			5	110	21	136
missense	2	14	308	34	11	369
nonsense	21	9				30
start loss						0
frameshift	29	4	1			34
inframe indel			11	3	1	15
splice donor/acceptor (+/-2bp)	9	11	1	1		22
splice region	3	1	20	24	6	54
non coding		2	4	115	74	195
Total	61	40	330	263	107

Highest pathogenic variant AF is 0.00000896

Variants in KDM6A

This is a list of pathogenic ClinVar variants found in the KDM6A region.

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

Position	Type	Phenotype	Significance	ClinVar
X-44873369-T-TGCC			Benign (Aug 13, 2019)
X-44873369-T-TGCCGCC			Likely benign (Aug 10, 2019)
X-44873502-C-G			Benign (Mar 19, 2020)
X-44873542-C-G		not specified	Uncertain significance (Jun 22, 2023)
X-44873542-C-T		not specified	Uncertain significance (Jun 20, 2024)
X-44873560-C-T			Uncertain significance (Sep 21, 2022)
X-44873571-C-G		Inborn genetic diseases	Uncertain significance (Jul 26, 2023)
X-44873574-TCGCTACCGCCGC-T		Kabuki syndrome 2	Uncertain significance (Nov 22, 2022)
X-44873575-C-G		Kabuki syndrome 2	Likely benign (Jul 03, 2022)
X-44873575-C-T			Likely benign (May 01, 2020)
X-44873574-T-TCGCTACCGCCGC		Kabuki syndrome 2 • KDM6A-related disorder • Inborn genetic diseases	Uncertain significance (Dec 20, 2023)
X-44873576-G-C		Kabuki syndrome 2	Uncertain significance (Jul 29, 2022)
X-44873578-T-TACCGCCGCCGCTGCC		Kabuki syndrome 2	Uncertain significance (Apr 28, 2021)
X-44873579-ACCGCCGCCGCTG-A		Kabuki syndrome 2	Benign (Nov 02, 2023)
X-44873579-A-ACCGCCGCCGCTG		Kabuki syndrome 2	Benign/Likely benign (Jan 19, 2024)
X-44873584-C-CGCCGCT		Kabuki syndrome 2	Uncertain significance (Sep 03, 2022)
X-44873587-C-G		KDM6A-related disorder	Likely benign (May 26, 2021)
X-44873587-C-CGCT		Kabuki syndrome 2	Uncertain significance (Nov 24, 2022)
X-44873590-T-TGCC		not specified • Kabuki syndrome 2	Benign/Likely benign (Jan 29, 2024)
X-44873590-T-TGCCGCC		Kabuki syndrome 2	Likely benign (Dec 17, 2022)
X-44873594-G-A		Kabuki syndrome 2	Uncertain significance (Jun 20, 2022)
X-44873598-C-G		KDM6A-related disorder	Uncertain significance (Jun 02, 2023)
X-44873599-C-G		Kabuki syndrome 2	Likely benign (Dec 25, 2021)
X-44873599-C-T		Kabuki syndrome 2	Likely benign (Dec 07, 2023)
X-44873600-G-A		Kabuki syndrome 2	Uncertain significance (Jun 01, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KDM6A	protein_coding	protein_coding	ENST00000377967	29	239091

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	7.20e-7	125723	0	5	125728	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.95	317	503	0.630	0.0000355	9172
Missense in Polyphen		45	147.27	0.30556		2860
Synonymous	0.0950	186	188	0.991	0.0000137	2687
Loss of Function	6.51	4	57.0	0.0702	0.00000443	926

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000722	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000502	0.0000352
Middle Eastern	0.0000722	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Histone demethylase that specifically demethylates 'Lys- 27' of histone H3, thereby playing a central role in histone code (PubMed:17851529, PubMed:17713478, PubMed:17761849). Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-27' (PubMed:17851529, PubMed:17713478, PubMed:17761849). Plays a central role in regulation of posterior development, by regulating HOX gene expression (PubMed:17851529). Demethylation of 'Lys-27' of histone H3 is concomitant with methylation of 'Lys-4' of histone H3, and regulates the recruitment of the PRC1 complex and monoubiquitination of histone H2A (PubMed:17761849). Plays a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression (By similarity). {ECO:0000250|UniProtKB:O70546, ECO:0000269|PubMed:17713478, ECO:0000269|PubMed:17761849, ECO:0000269|PubMed:17851529, ECO:0000269|PubMed:18003914}.
• Disease: DISEASE: Kabuki syndrome 2 (KABUK2) [MIM:300867]: A congenital mental retardation syndrome with additional features, including postnatal dwarfism, a peculiar facies characterized by long palpebral fissures with eversion of the lateral third of the lower eyelids, a broad and depressed nasal tip, large prominent earlobes, a cleft or high-arched palate, scoliosis, short fifth finger, persistence of fingerpads, radiographic abnormalities of the vertebrae, hands, and hip joints, and recurrent otitis media in infancy. {ECO:0000269|PubMed:22197486}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Transcriptional misregulation in cancer - Homo sapiens (human);Mesodermal Commitment Pathway;Pathways Affected in Adenoid Cystic Carcinoma;HDMs demethylate histones;Chromatin modifying enzymes;Chromatin organization (Consensus)

Recessive Scores

• pRec: 0.168

Intolerance Scores

• loftool: 0.187
• rvis_EVS: -0.07
• rvis_percentile_EVS: 48.78

Haploinsufficiency Scores

• pHI: 0.983
• hipred: Y
• hipred_score: 0.729
• ghis: 0.525

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.897

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Kdm6a
• Phenotype: neoplasm; 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; hematopoietic system 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); respiratory system phenotype; embryo phenotype; skeleton phenotype; immune system 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); muscle phenotype; growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype

Zebrafish Information Network

• Gene name: kdm6a
• Affected structure: ceratobranchial cartilage
• Phenotype tag: abnormal
• Phenotype quality: decreased size

Gene ontology

• Biological process: in utero embryonic development;neural tube closure;heart morphogenesis;respiratory system process;chromatin remodeling;positive regulation of gene expression;somite rostral/caudal axis specification;multicellular organism growth;mesodermal cell differentiation;notochord morphogenesis;histone H3-K4 methylation;oxidation-reduction process;canonical Wnt signaling pathway;histone H3-K27 demethylation;cardiovascular system development
• Cellular component: nucleus;nucleoplasm;histone methyltransferase complex;MLL3/4 complex
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;chromatin binding;chromatin DNA binding;histone demethylase activity;identical protein binding;sequence-specific DNA binding;metal ion binding;dioxygenase activity;histone demethylase activity (H3-K27 specific)