CHCHD4

protein-coding

coiled-coil-helix-coiled-coil-helix domain containing 4, the group of Coiled-coil-helix-coiled-coil-helix domain containing proteins

Gene summary

CHCHD4, a component of human mitochondria, belongs to a protein family whose members share 6 highly conserved cysteine residues constituting a -CXC-CX(9)C-CX(9)C- motif in the C terminus (Hofmann et al., 2005 [PubMed 16185709]).[supplied by OMIM, Mar 2008]

MANE transcript

NM_001098502.2

Inheritance

—

ClinVar variants

P:1U:19

Top phenotype

Abnormal brain lactate level by MRS

gnomAD constraint

pLI —, LoF o/e 0.3

Max pathogenic AF

—

Genomic locus

chr3:14,112,077-14,124,870

External References & Databases

Ensembl (ENSG00000163528)

Transcript & Mutation Effects

hg38 • Region Span ~12.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CHCHD4 variants in ClinVar

10 Conditions Cataloged

not specifiedTotal: 20

Abnormal brain lactate level by MRSTotal: 1

not providedTotal: 1

EncephalopathyTotal: 1

Lactic acidosisTotal: 1

Fetal growth restrictionTotal: 1

Global developmental delayTotal: 1

Decreased liver functionTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001098502.2. 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						0
missense	1 clinvar		18 clinvar			19
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	0	19	0	0	20

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001098502.2	RefSeq	NP_001091972.1	3	MANE Select
ENST00000396914.4	Ensembl	ENSP00000380122.3	3	MANE Select
NM_144636.3	RefSeq	NP_653237.1	3	Standard
ENST00000295767.9	Ensembl	ENSP00000295767.5	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of proteins
Mitochondrial protein import

Biological Process

peptidyl-cysteine oxidation
protein maturation by protein folding
protein import into mitochondrial intermembrane space
'de novo' posttranslational protein folding

Molecular Function

protein binding
protein disulfide oxidoreductase activity

Cellular Component

mitochondrion
mitochondrial intermembrane space

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000295767
Coding exons: 3
Length: 12791
Individuals with no LoFs: 125744
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125748
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.880	63	85.9	0.733	0.00000427	1023
Missense (PolyPhen)		14	22.852	0.61264		295
Synonymous	-0.653	36	31.3	1.15	0.00000183	271
Loss of Function	1.66	2	6.60	0.303	3.45e-7	76

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions as chaperone and catalyzes the formation of disulfide bonds in substrate proteins, such as COX17, COX19 and MICU1 (PubMed:16185709, PubMed:26387864, PubMed:19182799, PubMed:21059946, PubMed:23186364, PubMed:23676665). Required for the import and folding of small cysteine-containing proteins (small Tim) in the mitochondrial intermembrane space (IMS). Precursor proteins to be imported into the IMS are translocated in their reduced form into the mitochondria. The oxidized form of CHCHD4/MIA40 forms a transient intermolecular disulfide bridge with the reduced precursor protein, resulting in oxidation of the precursor protein that now contains an intramolecular disulfide bond and is able to undergo folding in the IMS (PubMed:16185709, PubMed:19182799, PubMed:21059946, PubMed:23676665). Reduced CHCHD4/MIA40 is then reoxidized by GFER/ERV1 via a disulfide relay system (PubMed:23186364). Mediates formation of disulfide bond in MICU1 in the IMS, promoting formation of the MICU1-MICU2 heterodimer that regulates mitochondrial calcium uptake (PubMed:26387864). {ECO:0000269|PubMed:16185709, ECO:0000269|PubMed:19182799, ECO:0000269|PubMed:21059946, ECO:0000269|PubMed:23186364, ECO:0000269|PubMed:23676665, ECO:0000269|PubMed:26387864}.;

Recessive Scores

pRec: 0.0959

Intolerance Scores

LoFtool: 0.312
RVIS EVS: -0.01
RVIS percentile EVS: 53.19

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.791

Gene Damage Prediction

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