CHAC1

protein-coding

ChaC glutathione specific gamma-glutamylcyclotransferase 1

Gene summary

This gene encodes a member of the gamma-glutamylcyclotransferase family of proteins. The encoded protein has been shown to promote neuronal differentiation by deglycination of the Notch receptor, which prevents receptor maturation and inhibits Notch signaling. This protein may also play a role in the unfolded protein response, and in regulation of glutathione levels and oxidative balance in the cell. Elevated expression of this gene may indicate increased risk of cancer recurrence among breast and ovarian cancer patients. [provided by RefSeq, Sep 2016]

MANE transcript

NM_024111.6

Inheritance

—

ClinVar variants

U:44B:1

Top phenotype

Prostate cancer

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr15:40,952,962-40,956,512

External References & Databases

Ensembl (ENSG00000128965)

Transcript & Mutation Effects

hg38 • Region Span ~3.6 kb

Loading mutation effect viewer...

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 CHAC1 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 38

not providedTotal: 1

Prostate cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024111.6. 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				1 clinvar		1
missense			41 clinvar			41
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	44	1	0	45

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_024111.6	RefSeq	NP_077016.3	3	MANE Select
ENST00000617768.5	Ensembl	ENSP00000484644.2	3	MANE Select
NM_001142776.4	RefSeq	NP_001136248.2	4	Standard
ENST00000444189.7	Ensembl	ENSP00000395466.3	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glutathione conjugation
Phase II - Conjugation of compounds
Biological oxidations
Metabolism
Glutathione synthesis and recycling

Biological Process

glutathione biosynthetic process
glutathione catabolic process
response to unfolded protein
Notch signaling pathway
negative regulation of protein processing

Molecular Function

gamma-glutamylcyclotransferase activity
Notch binding
protein binding
glutathione specific gamma-glutamylcyclotransferase activity

Cellular Component

cytoplasm
trans-Golgi network
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000446533
Coding exons: 3
Length: 3551
Individuals with no LoFs: 125716
Homozygous LoFs: 0
Heterozygous LoFs: 22
Defined: 125738
p: 0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.244	152	161	0.946	0.00000859	1677
Missense (PolyPhen)		51	64.044	0.79633		679
Synonymous	-0.221	73	70.6	1.03	0.00000421	564
Loss of Function	1.00	7	10.5	0.666	5.43e-7	97

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00018	0.00018	rare
South Asian	0	0.0	absent
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the cleavage of glutathione into 5-oxo-L- proline and a Cys-Gly dipeptide. Acts specifically on glutathione, but not on other gamma-glutamyl peptides (PubMed:27913623). Glutathione depletion is an important factor for apoptosis initiation and execution. Acts as a pro-apoptotic component of the unfolded protein response pathway by mediating the pro-apoptotic effects of the ATF4-ATF3-DDIT3/CHOP cascade (PubMed:19109178). Negative regulator of Notch signaling pathway involved in embryonic neurogenesis: acts by inhibiting Notch cleavage by furin, maintaining Notch in an immature inactive form, thereby promoting neurogenesis in embryos (PubMed:22445366). {ECO:0000269|PubMed:19109178, ECO:0000269|PubMed:22445366, ECO:0000269|PubMed:27913623}.;

Recessive Scores

pRec: 0.130

Intolerance Scores

LoFtool: 0.393
RVIS EVS: 0.86
RVIS percentile EVS: 88.69

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.600

Gene Damage Prediction

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