KDM2A

protein-coding

lysine demethylase 2A, the group of F-box and leucine rich repeat proteins|Zinc fingers CXXC-type|Lysine demethylases|PHD finger proteins

Gene summary

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains at least six highly degenerated leucine-rich repeats. This family member plays a role in epigenetic silencing. It nucleates at CpG islands and specifically demethylates both mono- and di-methylated lysine-36 of histone H3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

Previous symbols:

FBXL11

MANE transcript

NM_012308.3

Inheritance

ClinVar variants

P:20U:102B:2

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr11:67,119,263-67,258,082

External References & Databases

Ensembl (ENSG00000173120)

Transcript & Mutation Effects

hg38 • Region Span ~138.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KDM2A variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 79

not providedTotal: 18

KDM2A-related neurodevelopmental disorderTotal: 18

Neurodevelopmental disorderTotal: 2

KDM2A-related disorderTotal: 1

KDM2A related conditionTotal: 1

Cataract 4 multiple typesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012308.3. 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			1 clinvar	1 clinvar	1 clinvar	3
missense		9 clinvar	90 clinvar			99
nonsense	3 clinvar		3 clinvar			6
start loss						0
frameshift	7 clinvar	1 clinvar	1 clinvar			9
splice donor/acceptor (+/-2bp)			7 clinvar			7
Total	10	10	102	1	1	124

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012308.3	RefSeq	NP_036440.1	20	MANE Select
ENST00000529006.7	Ensembl	ENSP00000432786.1	20	MANE Select
NM_001256405.2	RefSeq	NP_001243334.1	10	Standard
ENST00000308783.10	Ensembl	ENSP00000309302.6	19	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
kdm2aa	Danio rerio	Structure: post-vent region Quality: present abnormal

Gene / Model

Organism

Observed Phenotype

kdm2aa

Danio rerio

Structure: post-vent region

Quality: present

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

The oncogenic action of Succinate
The oncogenic action of Fumarate
The oncogenic action of 2-hydroxyglutarate
The oncogenic action of L-2-hydroxyglutarate in Hydroxygluaricaciduria
The oncogenic action of D-2-hydroxyglutarate in Hydroxygluaricaciduria

Biological Process

double-strand break repair via nonhomologous end joining
regulation of transcription by RNA polymerase II
oxidation-reduction process
histone H3-K36 demethylation

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
protein binding
zinc ion binding
histone demethylase activity

Cellular Component

nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000529006
Coding exons: 20
Length: 138819
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.31	302	696	0.434	0.0000428	7615
Missense (PolyPhen)		40	261.68	0.15286		2818
Synonymous	-0.410	260	252	1.03	0.0000142	2247
Loss of Function	7.50	0	65.5	0.00	0.00000416	676

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Histone demethylase that specifically demethylates 'Lys- 36' of histone H3, thereby playing a central role in histone code. Preferentially demethylates dimethylated H3 'Lys-36' residue while it has weak or no activity for mono- and tri-methylated H3 'Lys- 36'. May also recognize and bind to some phosphorylated proteins and promote their ubiquitination and degradation. Required to maintain the heterochromatic state. Associates with centromeres and represses transcription of small non-coding RNAs that are encoded by the clusters of satellite repeats at the centromere. Required to sustain centromeric integrity and genomic stability, particularly during mitosis. {ECO:0000269|PubMed:16362057, ECO:0000269|PubMed:19001877, ECO:0000269|PubMed:28262558}.;

Recessive Scores

pRec: 0.104

Intolerance Scores

LoFtool: 0.0344
RVIS EVS: -1.2
RVIS percentile EVS: 5.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.668

Gene Damage Prediction

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