JARID2

protein-coding

jumonji and AT-rich interaction domain containing 2, the group of AT-rich interaction domain containing|Iron (II) and 2-oxoglutarate dependent oxygenases

Gene summary

This gene encodes a Jumonji- and AT-rich interaction domain (ARID)-domain-containing protein. The encoded protein is a DNA-binding protein that functions as a transcriptional repressor. This protein interacts with the Polycomb repressive complex 2 (PRC2) which plays an essential role in regulating gene expression during embryonic development. This protein facilitates the recruitment of the PRC2 complex to target genes. Alternate splicing results in multiple transcript variants. Mutations in this gene are associated with chronic myeloid malignancies. [provided by RefSeq, May 2012]

Previous symbols:

MANE transcript

NM_004973.4

Inheritance

ClinVar variants

P:27U:249B:84

Top phenotype

Developmental delay with variable intellecutal disability and dysmorphic facies

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr6:15,246,069-15,522,042

External References & Databases

Ensembl (ENSG00000008083)

Transcript & Mutation Effects

hg38 • Region Span ~276.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental delay with variable intellectual disability and dysmorphic faciesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859306

Submitter: G2P

syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: Orphanet

developmental delay with variable intellectual disability and dysmorphic faciesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0859306

Submitter: ClinGen

*JARID2* was first reported in relation to autosomal dominant developmental delay with variable intellectual disability and dysmorphic facies in 2021 (Verberne et al., PMID: 33077894). Phenotypic features reported in affected individuals include developmental delay, intellectual disability, autism spectrum disorders (ASD), behavioral abnormalities and dysmorphic features including high anterior hairline, deep-set eyes, full lips, broad forehead, bulbous nasal tip, and depressed nasal bridge. Twenty-three variants (nonsense, frameshift and exon deletion variants) that have been reported in 23 probands in 3 publications (PMIDs: 33077894, 35887345, 35533077) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function that disrupts genome wide methylation as demonstrated by an abnormal methylation signature pattern in probands with JARID2 pathogenic variants (PMID: 35887345). In summary, there is definitive evidence to support the relationship between *JARID2* and autosomal dominant developmental delay with variable intellectual disability and dysmorphic facies. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 6, 2024 (SOP Version 10).

developmental delay with variable intellectual disability and dysmorphic faciesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859306

Submitter: Labcorp Genetics (formerly Invitae)

developmental delay with variable intellectual disability and dysmorphic faciesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859306

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Developmental delay with variable intellecutal disability and dysmorphic faciesAD

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, prognostic considerations, and avoidance of unnecessary testing

Refs: 33077894; 35533077; 35887345

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to JARID2 variants in ClinVar

17 Conditions Cataloged

Inborn genetic diseasesTotal: 173

not providedTotal: 119

Developmental delay with variable intellectual disability and dysmorphic faciesTotal: 32

JARID2-related disorderTotal: 29

not specifiedTotal: 10

Neurodevelopmental disorderTotal: 3

JARID2-associated Neurodevelopmental disorderTotal: 2

JARID2-related Neurodevelopmental syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004973.4. 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			6 clinvar	32 clinvar	10 clinvar	48
missense		1 clinvar	232 clinvar	38 clinvar	4 clinvar	275
nonsense	5 clinvar	2 clinvar	3 clinvar			10
start loss		1 clinvar				1
frameshift	10 clinvar	6 clinvar	2 clinvar			18
splice donor/acceptor (+/-2bp)		2 clinvar	6 clinvar			8
Total	15	12	249	70	14	360

Highest pathogenic variant AF is 0.000004338282

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 50 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004973.4	RefSeq	NP_004964.2	18	MANE Select
ENST00000341776.7	Ensembl	ENSP00000341280.2	18	MANE Select
NM_001267040.1	RefSeq	NP_001253969.1	14	Standard
ENST00000397311.4	Ensembl	ENSP00000380478.3	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
Endoderm Differentiation
Mesodermal Commitment Pathway
Interactome of polycomb repressive complex 2 (PRC2)
Epigenetic regulation of gene expression

Biological Process

negative regulation of transcription by RNA polymerase II
liver development
chromatin remodeling
central nervous system development
negative regulation of cardiac muscle hypertrophy

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
chromatin binding
transcription factor binding
histone demethylase activity

Cellular Component

nucleus
nucleoplasm
mitochondrion
histone methyltransferase complex
ESC/E(Z) complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000341776
Coding exons: 18
Length: 275726
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125748
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.69	575	787	0.731	0.0000510	8125
Missense (PolyPhen)		117	243.77	0.47996		2466
Synonymous	-2.12	383	334	1.15	0.0000241	2482
Loss of Function	6.31	5	55.9	0.0894	0.00000291	654

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)	0.000062	0.000062	rare
South Asian	0	0.0	absent
Other	0.00033	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulator of histone methyltransferase complexes that plays an essential role in embryonic development, including heart and liver development, neural tube fusion process and hematopoiesis. Acts by modulating histone methyltransferase activity and promoting the recruitment of histone methyltransferase complexes to their target genes. Binds DNA and mediates the recruitment of the PRC2 complex to target genes in embryonic stem cells. Does not have histone demethylase activity but regulates activity of various histone methyltransferase complexes. In embryonic stem cells, it associates with the PRC2 complex and inhibits trimethylation of 'Lys-27' of histone H3 (H3K27me3) by the PRC2 complex, thereby playing a key role in differentiation of embryonic stem cells and normal development. In cardiac cells, it is required to repress expression of cyclin-D1 (CCND1) by activating methylation of 'Lys-9' of histone H3 (H3K9me) by the GLP1/EHMT1 and G9a/EHMT2 histone methyltransferases. Also acts as a transcriptional repressor of ANF via its interaction with GATA4 and NKX2-5. Participates in the negative regulation of cell proliferation signaling. {ECO:0000269|PubMed:20075857}.;

Recessive Scores

pRec: 0.182

Intolerance Scores

LoFtool: 0.0413
RVIS EVS: -1.74
RVIS percentile EVS: 2.42

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.955

Gene Damage Prediction

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