KDM5A
protein-codinglysine demethylase 5A, the group of AT-rich interaction domain containing|PHD finger proteins|EMSY complex|Lysine demethylases
Gene summary
This gene encodes a member of the Jumonji, AT-rich interactive domain 1 (JARID1) histone demethylase protein family. The encoded protein plays a role in gene regulation through the histone code by specifically demethylating lysine 4 of histone H3. The encoded protein interacts with many other proteins, including retinoblastoma protein, and is implicated in the transcriptional regulation of Hox genes and cytokines. This gene may play a role in tumor progression. [provided by RefSeq, Aug 2013]
- RBBP2
- JARID1A
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~109.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0700092
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0700092
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0970951
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0005453
Submitter: ClinGen
*KDM5A* was first reported in relation to autosomal dominant congenital heart disease in 2013 (Zaidi et al., PMID: 23665959). Three unique variants (missense and frameshift) in three individuals with congenital heart disease that have been reported in three publications (PMIDs: 23665959, 28991257, 33084842) were included in this curation. No experimental evidence has been reported in the literature supporting this gene-disease relationship. In summary, there is limited evidence supporting the relationship between *KDM5A* and autosomal dominant congenital heart disease. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 1/8/2024 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0700092
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0970951
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Neurologic
Intervention: Cardiovascular
Rationale: Among other findings, the condition may involve congenital cardiovascular anomalies, and awareness may allow early identification and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to KDM5A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001042603.3. 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 | 3 | 33 | 3 | 39 | ||
| missense | 1 | 1 | 213 | 8 | 5 | 228 |
| nonsense | 1 | 3 | 6 | 10 | ||
| start loss | 1 | 1 | ||||
| frameshift | 2 | 2 | 5 | 9 | ||
| splice donor/acceptor (+/-2bp) | 2 | 2 | 14 | 18 | ||
| Total | 6 | 9 | 241 | 41 | 8 | 305 |
Highest pathogenic variant AF is 0.000015497744
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001036068.1 | 28 | MANE Select | |
| Ensembl | ENSP00000382688.2 | 28 | MANE Select | |
| Ensembl | ENSP00000443854.1 | 3 | Standard | |
| Ensembl | ENSP00000438203.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- HDMs demethylate histones
- Chromatin modifying enzymes
- Chromatin organization
Biological Process
- negative regulation of transcription by RNA polymerase II
- chromatin remodeling
- spermatogenesis
- male gonad development
- circadian regulation of gene expression
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- core promoter sequence-specific DNA binding
- DNA binding
- DNA-binding transcription factor activity
- transcription coactivator activity
Cellular Component
- nucleus
- nucleoplasm
- nucleolus
- protein-DNA complex
- histone methyltransferase complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000399788
- Coding exons
- 28
- Length
- 109326
- Individuals with no LoFs
- 125178
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 16
- Defined
- 125194
- p
- 0.0000639
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.25 | 718 | 909 | 0.790 | 0.0000507 | 11118 |
| Missense (PolyPhen) | 134 | 271.67 | 0.49325 | 3412 | ||
| Synonymous | -2.66 | 384 | 323 | 1.19 | 0.0000169 | 3216 |
| Loss of Function | 7.94 | 8 | 88.7 | 0.0902 | 0.00000509 | 1047 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000080 | 0.000079 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Histone demethylase that specifically demethylates 'Lys- 4' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. Regulates specific gene transcription through DNA-binding on 5'-CCGCCC-3' motif (PubMed:18270511). May stimulate transcription mediated by nuclear receptors. Involved in transcriptional regulation of Hox proteins during cell differentiation (PubMed:19430464). May participate in transcriptional repression of cytokines such as CXCL12. Plays a role in the regulation of the circadian rhythm and in maintaining the normal periodicity of the circadian clock. In a histone demethylase-independent manner, acts as a coactivator of the CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER1/2 and other clock-controlled genes and increases histone acetylation at PER1/2 promoters by inhibiting the activity of HDAC1 (By similarity). Seems to act as a transcriptional corepressor for some genes such as MT1F and to favor the proliferation of cancer cells (PubMed:27427228). {ECO:0000250|UniProtKB:Q3UXZ9, ECO:0000269|PubMed:11358960, ECO:0000269|PubMed:15949438, ECO:0000269|PubMed:17320160, ECO:0000269|PubMed:17320161, ECO:0000269|PubMed:17320163, ECO:0000269|PubMed:18270511, ECO:0000269|PubMed:19430464, ECO:0000269|PubMed:27427228}.;
Recessive Scores
- pRec
- 0.161
Intolerance Scores
- LoFtool
- 0.0591
- RVIS EVS
- -0.74
- RVIS percentile EVS
- 13.79
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.835
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |