APAF1

protein-coding

apoptotic peptidase activating factor 1, the group of WD repeat domain containing|Caspase recruitment domain containing|Apoptosome

Gene summary

This gene encodes a cytoplasmic protein that initiates apoptosis. This protein contains several copies of the WD-40 domain, a caspase recruitment domain (CARD), and an ATPase domain (NB-ARC). Upon binding cytochrome c and dATP, this protein forms an oligomeric apoptosome. The apoptosome binds and cleaves caspase 9 preproprotein, releasing its mature, activated form. Activated caspase 9 stimulates the subsequent caspase cascade that commits the cell to apoptosis. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

MANE transcript

NM_181861.2

Inheritance

ClinVar variants

U:128B:23

Top phenotype

APAF1-related disorder

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr12:98,645,149-98,735,433

External References & Databases

Ensembl (ENSG00000120868)

Transcript & Mutation Effects

hg38 • Region Span ~90.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

depressive disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0002050

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to APAF1 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 122

APAF1-related disorderTotal: 21

not providedTotal: 13

Inborn genetic diseasesTotal: 2

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

Neural tube defectTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_181861.2. 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				7 clinvar	3 clinvar	10
missense			122 clinvar	7 clinvar	6 clinvar	135
nonsense			1 clinvar			1
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	128	14	9	151

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_181861.2	RefSeq	NP_863651.1	26	MANE Select
ENST00000551964.6	Ensembl	ENSP00000448165.2	26	MANE Select
NM_001160.3	RefSeq	NP_001151.1	25	Standard
NM_013229.3	RefSeq	NP_037361.1	26	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Legionellosis - Homo sapiens (human)
p53 signaling pathway - Homo sapiens (human)
Small cell lung cancer - Homo sapiens (human)
Apoptosis - multiple species - Homo sapiens (human)
Alzheimer,s disease - Homo sapiens (human)

Biological Process

response to hypoxia
kidney development
neural tube closure
apoptotic process
activation of cysteine-type endopeptidase activity involved in apoptotic process

Molecular Function

nucleotide binding
protein binding
ATP binding
cysteine-type endopeptidase activator activity involved in apoptotic process
heat shock protein binding

Cellular Component

extracellular region
nucleus
cytosol
protein-containing complex
secretory granule lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000551964
Coding exons: 26
Length: 90286
Individuals with no LoFs: 125620
Homozygous LoFs: 0
Heterozygous LoFs: 128
Defined: 125748
p: 0.000509

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.43	544	646	0.841	0.0000323	8276
Missense (PolyPhen)		107	184.08	0.58127		2366
Synonymous	-0.402	234	226	1.03	0.0000117	2277
Loss of Function	5.14	22	67.7	0.325	0.00000322	844

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0020	0.0020	notable
Latino/Admixed American	0.00038	0.00038	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00044	0.00044	rare
South Asian	0.00079	0.00078	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Oligomeric Apaf-1 mediates the cytochrome c-dependent autocatalytic activation of pro-caspase-9 (Apaf-3), leading to the activation of caspase-3 and apoptosis. This activation requires ATP. Isoform 6 is less effective in inducing apoptosis. {ECO:0000269|PubMed:10393175, ECO:0000269|PubMed:12804598}.;

Recessive Scores

pRec: 0.545

Intolerance Scores

LoFtool: 0.456
RVIS EVS: -0.08
RVIS percentile EVS: 47.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.694

Gene Damage Prediction

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