KDM5B

protein-coding

lysine demethylase 5B, the group of AT-rich interaction domain containing|PHD finger proteins|Lysine demethylases

Gene summary

This gene encodes a lysine-specific histone demethylase that belongs to the jumonji/ARID domain-containing family of histone demethylases. The encoded protein is capable of demethylating tri-, di- and monomethylated lysine 4 of histone H3. This protein plays a role in the transcriptional repression or certain tumor suppressor genes and is upregulated in certain cancer cells. This protein may also play a role in genome stability and DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

Previous symbols:

JARID1B

MANE transcript

NM_006618.5

Inheritance

AR, AD, SD

ClinVar variants

P:123U:350B:78

Top phenotype

Intellectual developmental disorder, autosomal recessive 65

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr1:202,724,495-202,808,487

External References & Databases

Ensembl (ENSG00000117139)

Transcript & Mutation Effects

hg38 • Region Span ~84.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

intellectual developmental disorder, autosomal recessive 65LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0020850

Submitter: Ambry Genetics

Tourette syndromeNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0007661

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal recessive 65STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020850

Submitter: Labcorp Genetics (formerly Invitae)

intellectual disabilityMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0001071

Submitter: ClinGen

*KDM5B* was first reported in relation to autosomal recessive intellectual disability in 2018 (Faundes, et al., PMID: 29276005). At least 9 unique variants (e.g. missense, nonsense, frameshift, splice site, large deletion, etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, and experimental evidence. Variants in this gene have been reported in at least 5 probands in 3 publications (PMIDs: 29276005, 34573379, 30409806). Nine variants (missense, nonsense, frameshift, splice site, large deletion) that have been reported in 5 probands in 3 publications (PMIDs: 29276005, 34573379, 30409806) are included in this curation. Please note that due to limitations of the scoring interface, a proband who was compound heterozygous for a splice variant and a large deletion was not able to be formally entered and scored at 2 points (PMID:30409806). This gene-disease association is also supported by animal models, in vitro functional assays, and biochemical function studies (PMIDs: 30409806, 22020125). Of note, this gene has also been implicated in autosomal dominant intellectual disability, autism, and development disorder. These will be assessed separately. Although this curation reached Definitive, the classification has been modified to Moderate due to the small number of probands reported in the literature. More evidence is needed to establish this relationship definitively. In summary, there is moderate evidence to support this gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 3/1/2022 (SOP Version 8).

neurodevelopmental disorderSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal recessive 65STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020850

Submitter: G2P

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 65AR

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision making, and avoidance of unnecessary testing

Comments: Heterozygous variants appear to be able to cause an incompletely penetrant phenotype

Refs: 29276005; 30409806

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KDM5B variants in ClinVar

16 Conditions Cataloged

not providedTotal: 257

Inborn genetic diseasesTotal: 197

Intellectual disability, autosomal recessive 65Total: 95

KDM5B-related disorderTotal: 51

not specifiedTotal: 22

Neurodevelopmental disorderTotal: 10

Intellectual disabilityTotal: 3

See casesTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006618.5. 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			2 clinvar	56 clinvar	5 clinvar	63
missense	1 clinvar	9 clinvar	311 clinvar	16 clinvar	1 clinvar	338
nonsense	13 clinvar	34 clinvar	9 clinvar			56
start loss						0
frameshift	19 clinvar	29 clinvar	13 clinvar			61
splice donor/acceptor (+/-2bp)	3 clinvar	15 clinvar	15 clinvar			33
Total	36	87	350	72	6	551

Highest pathogenic variant AF is 0.00004275326

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 57 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006618.5	RefSeq	NP_006609.3	27	MANE Select
ENST00000367265.9	Ensembl	ENSP00000356234.3	27	MANE Select
NM_001314042.2	RefSeq	NP_001300971.1	28	Standard
NM_001347591.2	RefSeq	NP_001334520.1	26	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gene expression (Transcription)
Generic Transcription Pathway
HDMs demethylate histones
RNA Polymerase II Transcription
Chromatin modifying enzymes

Biological Process

negative regulation of transcription by RNA polymerase II
chromatin remodeling
regulation of transcription by RNA polymerase II
single fertilization
post-embryonic development

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
DNA-binding transcription factor activity
transcription corepressor activity
protein binding

Cellular Component

nucleus
nucleoplasm
cytosol
histone methyltransferase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367265
Coding exons: 27
Length: 82073
Individuals with no LoFs: 125620
Homozygous LoFs: 0
Heterozygous LoFs: 128
Defined: 125748
p: 0.000509

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.78	701	847	0.828	0.0000454	10098
Missense (PolyPhen)		226	331.32	0.68212		3976
Synonymous	0.822	294	312	0.941	0.0000159	2954
Loss of Function	4.96	40	91.1	0.439	0.00000581	989

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.0024	0.0024	notable
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00044	0.00043	rare
South Asian	0.00027	0.00026	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Histone demethylase that demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code (PubMed:24952722, PubMed:27214403, PubMed:28262558). Does not demethylate histone H3 'Lys-9' or H3 'Lys-27'. Demethylates trimethylated, dimethylated and monomethylated H3 'Lys-4'. Acts as a transcriptional corepressor for FOXG1B and PAX9. Favors the proliferation of breast cancer cells by repressing tumor suppressor genes such as BRCA1 and HOXA5 (PubMed:24952722). In contrast, may act as a tumor suppressor for melanoma. Represses the CLOCK-ARNTL/BMAL1 heterodimer-mediated transcriptional activation of the core clock component PER2 (By similarity). {ECO:0000250|UniProtKB:Q80Y84, ECO:0000269|PubMed:12657635, ECO:0000269|PubMed:16645588, ECO:0000269|PubMed:17320161, ECO:0000269|PubMed:17363312, ECO:0000269|PubMed:24952722, ECO:0000269|PubMed:26645689, ECO:0000269|PubMed:26741168, ECO:0000269|PubMed:27214403, ECO:0000269|PubMed:28262558}.;

Recessive Scores

pRec: 0.128

Intolerance Scores

LoFtool: 0.176
RVIS EVS: -1.72
RVIS percentile EVS: 2.48

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.636

Gene Damage Prediction

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