CHD5

protein-coding

chromodomain helicase DNA binding protein 5, the group of PHD finger proteins|NuRD complex subunits

Gene summary

This gene encodes a member of the chromodomain helicase DNA-binding protein family. Members of this family are characterized by a chromodomain, a helicase ATP-binding domain and an additional functional domain. This gene encodes a neuron-specific protein that may function in chromatin remodeling and gene transcription. This gene is a potential tumor suppressor gene that may play a role in the development of neuroblastoma. [provided by RefSeq, Feb 2012]

MANE transcript

NM_015557.3

Inheritance

ClinVar variants

P:48U:482B:79

Top phenotype

Parenti-Mignot neurodevelopmental syndrome

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr1:6,101,787-6,180,321

External References & Databases

Ensembl (ENSG00000116254)

Transcript & Mutation Effects

hg38 • Region Span ~78.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

parenti-mignot neurodevelopmental syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859249

Submitter: Ambry Genetics

parenti-mignot neurodevelopmental syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859249

Submitter: Labcorp Genetics (formerly Invitae)

parenti-mignot neurodevelopmental syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0859249

Submitter: G2P

schizophreniaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0005090

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Parenti-Mignot neurodevelopmental syndromeAD

Manifestation: Craniofacial; 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: 33944996

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CHD5 variants in ClinVar

17 Conditions Cataloged

not providedTotal: 279

Inborn genetic diseasesTotal: 213

Parenti-mignot neurodevelopmental syndromeTotal: 91

CHD5-related disorderTotal: 67

not specifiedTotal: 60

Global developmental delayTotal: 14

SeizureTotal: 10

Intellectual disabilityTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015557.3. 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			5 clinvar	58 clinvar	4 clinvar	67
missense		22 clinvar	464 clinvar	17 clinvar		503
nonsense	5 clinvar	6 clinvar	5 clinvar			16
start loss			1 clinvar			1
frameshift	4 clinvar	6 clinvar	1 clinvar			11
splice donor/acceptor (+/-2bp)		5 clinvar	6 clinvar			11
Total	9	39	482	75	4	609

Highest pathogenic variant AF is 0.000013143368

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015557.3	RefSeq	NP_056372.1	41	MANE Select
ENST00000262450.8	Ensembl	ENSP00000262450.3	41	MANE Select
ENST00000377999.5	Ensembl	ENSP00000367238.2	3	Standard
ENST00000462991.5	Ensembl	ENSP00000466706.1	24	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
chd5	Danio rerio	Structure: splanchnocranium Quality: absent abnormal

Gene / Model

Organism

Observed Phenotype

chd5

Danio rerio

Structure: splanchnocranium

Quality: absent

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of cell population proliferation
cerebral cortex neuron differentiation
spermatogenesis, exchange of chromosomal proteins
histone H4 acetylation
regulation of transcription involved in cell fate commitment

Molecular Function

DNA binding
helicase activity
ATP binding
metal ion binding
H3K27me3 modified histone binding

Cellular Component

heterochromatin
nucleus
nucleoplasm
cytosol
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262450
Coding exons: 41
Length: 78331
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125748
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.32	668	1.18e+3	0.565	0.0000749	12905
Missense (PolyPhen)		143	453.16	0.31556		4698
Synonymous	-0.0510	518	517	1.00	0.0000371	3624
Loss of Function	8.44	9	100	0.0898	0.00000515	1178

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000061	0.000054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.000080	0.000079	rare
South Asian	0.00010	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Chromatin-remodeling protein that binds DNA through histones and regulates gene transcription. May specifically recognize and bind trimethylated 'Lys-27' (H3K27me3) and non- methylated 'Lys-4' of histone H3. Plays a role in the development of the nervous system by activating the expression of genes promoting neuron terminal differentiation. In parallel, it may also positively regulate the trimethylation of histone H3 at 'Lys- 27' thereby specifically repressing genes that promote the differentiation into non-neuronal cell lineages. Tumor suppressor, it regulates the expression of genes involved in cell proliferation and differentiation. Downstream activated genes may include CDKN2A that positively regulates the p53/TP53 pathway, which in turn, prevents cell proliferation. In spermatogenesis, it probably regulates histone hyperacetylation and the replacement of histones by transition proteins in chromatin, a crucial step in the condensation of spermatid chromatin and the production of functional spermatozoa. {ECO:0000269|PubMed:23948251}.;
Disease: DISEASE: Note=Defects in CHD5 may be a cause of the development of cancers from epithelial, neural and hematopoietic origin. CHD5 is one of the missing genes in the del(1p36), a deletion which is extremely common in this type of cancers. A decrease of its expression, results in increased susceptibility of cells to Ras- mediated transformation in vitro and in vivo (PubMed:17289567). {ECO:0000269|PubMed:17289567}.;

Recessive Scores

pRec: 0.116

Intolerance Scores

LoFtool: 0.0144
RVIS EVS: -3.07
RVIS percentile EVS: 0.49

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.256

Gene Damage Prediction

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