ATG4D

protein-coding

autophagy related 4D cysteine peptidase, the group of MicroRNA protein coding host genes|Autophagy related

Gene summary

Autophagy is the process by which endogenous proteins and damaged organelles are destroyed intracellularly. Autophagy is postulated to be essential for cell homeostasis and cell remodeling during differentiation, metamorphosis, non-apoptotic cell death, and aging. Reduced levels of autophagy have been described in some malignant tumors, and a role for autophagy in controlling the unregulated cell growth linked to cancer has been proposed. This gene belongs to the autophagy-related protein 4 (Atg4) family of C54 endopeptidases. Members of this family encode proteins that play a role in the biogenesis of autophagosomes, which sequester the cytosol and organelles for degradation by lysosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

Previous symbols:

AUTL4
APG4D

MANE transcript

NM_032885.6

Inheritance

ClinVar variants

P:7U:88B:7

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr19:10,543,895-10,553,418

External References & Databases

Ensembl (ENSG00000130734)

Transcript & Mutation Effects

hg38 • Region Span ~9.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

neurodevelopmental disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: G2P

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATG4D variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 85

not providedTotal: 6

Spermatogenic failure 101Total: 5

ASHERTotal: 3

ATG4D-related conditionTotal: 2

ATG4D-related neurodevelopmental conditionTotal: 2

Neurodevelopmental disorderTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032885.6. 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			2 clinvar	3 clinvar		5
missense	4 clinvar	2 clinvar	83 clinvar	4 clinvar		93
nonsense						0
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	4	3	88	7	0	102

Highest pathogenic variant AF is 0.000989991

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032885.6	RefSeq	NP_116274.3	10	MANE Select
ENST00000309469.9	Ensembl	ENSP00000311318.3	10	MANE Select
NM_001281504.2	RefSeq	NP_001268433.1	9	Standard
ENST00000585437.1	Ensembl	ENSP00000467694.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
atg4da	Danio rerio	Structure: Purkinje cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

atg4da

Danio rerio

Structure: Purkinje cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Autophagy - animal - Homo sapiens (human)
Autophagy - other - Homo sapiens (human)
Macroautophagy
Cellular responses to external stimuli

Biological Process

proteolysis
autophagy
apoptotic process
protein transport

Molecular Function

cysteine-type peptidase activity

Cellular Component

cytoplasm
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000309469
Coding exons: 10
Length: 9524
Individuals with no LoFs: 125701
Homozygous LoFs: 0
Heterozygous LoFs: 47
Defined: 125748
p: 0.000187

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.804	241	279	0.864	0.0000184	3015
Missense (PolyPhen)		84	97.537	0.86121		1073
Synonymous	0.496	104	111	0.940	0.00000680	992
Loss of Function	2.60	10	23.7	0.423	0.00000118	252

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00033	0.00033	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0.000068	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cysteine protease ATG4D: Cysteine protease required for the cytoplasm to vacuole transport (Cvt) and autophagy. Cleaves the C-terminal amino acid of ATG8 family proteins MAP1LC3 and GABARAPL2, to reveal a C-terminal glycine. Exposure of the glycine at the C-terminus is essential for ATG8 proteins conjugation to phosphatidylethanolamine (PE) and insertion to membranes, which is necessary for autophagy. Has also an activity of delipidating enzyme for the PE-conjugated forms.;

Recessive Scores

pRec: 0.106

Intolerance Scores

LoFtool: 0.348
RVIS EVS: -0.58
RVIS percentile EVS: 18.72

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.470

Gene Damage Prediction

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