CHD3

Chr 17AD

chromodomain helicase DNA binding protein 3

Also known as: Mi-2a, Mi2-ALPHA, SNIBCPS, ZFH

NCBI Gene: 1107 ENSG00000170004 UniProt: Q12873 OMIM: 602120

This protein functions as a component of the Mi-2/NuRD complex, which remodels chromatin by deacetylating histones and is essential for transcriptional regulation. Loss-of-function mutations cause Snijders Blok-Campeau syndrome through an autosomal dominant inheritance pattern. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the pathogenic mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the CHD family of proteins which are characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. This protein is one of the components of a histone deacetylase complex referred to as the Mi-2/NuRD complex which participates in the remodeling of chromatin by deacetylating histones. Chromatin remodeling is essential for many processes including transcription. Autoantibodies against this protein are found in a subset of patients with dermatomyositis. Three alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.151 OMIM phenotype

Clinical Summary— CHD3

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Gene-Disease Validity (ClinGen)

Snijders Blok-Campeau syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

124 unique Pathogenic / Likely Pathogenic· 517 VUS of 850 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.15LOEUF

pLI 1.000

Z-score 9.10

OE 0.09 (0.05–0.15)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

6.15Z-score

OE missense 0.50 (0.46–0.53)

591 obs / 1187.6 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.09 (0.05–0.15)

0≤0.351.4

Missense OE?0.50 (0.46–0.53)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 10 / 115.5Missense obs/exp: 591 / 1187.6Syn Z: 0.04

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCHD3-related macrocephaly and impaired speech and languageOTHERAD

This gene — mechanism propensity

0.3991th %ile

GOF

0.4085th %ile

LOF

0.68top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 40% of P/LP variants are LoF · LOEUF 0.15

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

850 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37

Likely Pathogenic87

VUS517

Likely Benign126

Benign19

Conflicting32

Pathogenic

Likely Pathogenic

517

VUS

126

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	26	10	1	0	37
Likely Pathogenic	24	62	0	1	87
VUS	11	485	17	4	517
Likely Benign	0	62	15	49	126
Benign	0	4	6	9	19
Conflicting	—				32
Total	61	623	39	63	818

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

21 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap CHD3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →