PLA2G4A

protein-coding

phospholipase A2 group IVA, the group of Phospholipases|C2 domain containing phospholipases

Gene summary

This gene encodes a member of the cytosolic phospholipase A2 group IV family. The enzyme catalyzes the hydrolysis of membrane phospholipids to release arachidonic acid which is subsequently metabolized into eicosanoids. Eicosanoids, including prostaglandins and leukotrienes, are lipid-based cellular hormones that regulate hemodynamics, inflammatory responses, and other intracellular pathways. The hydrolysis reaction also produces lysophospholipids that are converted into platelet-activating factor. The enzyme is activated by increased intracellular Ca(2+) levels and phosphorylation, resulting in its translocation from the cytosol and nucleus to perinuclear membrane vesicles. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

Previous symbols:

PLA2G4

MANE transcript

NM_024420.3

Inheritance

AR, AD

ClinVar variants

P:6U:63B:78

Top phenotype

Gastrointestinal ulceration, recurrent, with dysfunctional platelets

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr1:186,828,949-186,988,981

External References & Databases

Ensembl (ENSG00000116711)

Transcript & Mutation Effects

hg38 • Region Span ~160.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cytosolic phospholipase-A2 alpha deficiency associated bleeding disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0018794

Submitter: Ambry Genetics

cytosolic phospholipase-A2 alpha deficiency associated bleeding disorderSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018794

Submitter: Orphanet

cytosolic phospholipase-A2 alpha deficiency associated bleeding disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018794

Submitter: Labcorp Genetics (formerly Invitae)

cytosolic phospholipase-A2 alpha deficiency associated bleeding disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018794

Submitter: PanelApp Australia

cytosolic phospholipase-A2 alpha deficiency associated bleeding disorderMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0018794

Submitter: ClinGen

PLA2G4A was first reported in relation to autosomal recessive cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder in 2008 (Adler DH, et al., 2008, PMID: 18451993). At least four unique variants (3 missense and 1 intronic) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least three probands in three publications (PMIDs: 18451993, 23268370, 25102815). Variants in this gene segregated with disease in two additional family members. This gene-disease relationship is supported by its biochemical function in the release of arachidonic acid (PMID: 3143418), functional alteration in both patient (PMID: 26183771) and non-patient cells (PMID: 21247147), and a mouse model (PMID: 12163563). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was orginally evaluated by the HT GCEP on 03/25/2020 and reevaluated on 06/22/2022. It was again reevaluated on 10/21/2024 and as a result of this reevaluation the classification did not change as no new information is contributing to the classification.

cryptogenic multifocal ulcerous stenosing enteritisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018765

Submitter: Orphanet

Clinical Genomic Database (CGD)

Gastrointestinal ulceration, recurrent, with dysfunctional plateletsAR

Manifestation: Gastrointestinal; Hematologic

Intervention: Gastrointestinal; Hematologic

Rationale: Surveillance for bleeding complications may be beneficial, as a described individual had chronic GI blood loss from childhood, with multiple small intestinal ulcers discovered in the context of severe bleeding and perforations during adulthood; Awareness of GI complications, including Cryptogenic multifocal ulcerating stenosing enteritis, as has been described in one pair of siblings, may allow early medical and/or surgical management

Refs: 18451993; 23268370

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLA2G4A variants in ClinVar

4 Conditions Cataloged

not providedTotal: 164

not specifiedTotal: 56

PLA2G4A-related disorderTotal: 8

Cytosolic phospholipase-A2 alpha deficiency associated bleeding disorderTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024420.3. 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				65 clinvar	3 clinvar	68
missense	3 clinvar		59 clinvar	7 clinvar	3 clinvar	72
nonsense						0
start loss						0
frameshift		2 clinvar	2 clinvar			4
splice donor/acceptor (+/-2bp)	1 clinvar		2 clinvar			3
Total	4	2	63	72	6	147

Highest pathogenic variant AF is 0.0000027364686

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024420.3	RefSeq	NP_077734.2	17	MANE Select
ENST00000367466.4	Ensembl	ENSP00000356436.3	17	MANE Select
NM_001311193.2	RefSeq	NP_001298122.2	15	Standard
ENST00000851114.1	Ensembl	ENSP00000521173.1	17	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pla2g4aa	Danio rerio	Structure: otic vesicle Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

pla2g4aa

Danio rerio

Structure: otic vesicle

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Inflammatory mediator regulation of TRP channels - Homo sapiens (human)
Platelet activation - Homo sapiens (human)
Oxytocin signaling pathway - Homo sapiens (human)
Fc epsilon RI signaling pathway - Homo sapiens (human)
Fc gamma R-mediated phagocytosis - Homo sapiens (human)

Biological Process

phospholipid metabolic process
phosphatidic acid biosynthetic process
platelet activating factor biosynthetic process
icosanoid metabolic process
arachidonic acid metabolic process

Molecular Function

lysophospholipase activity
phospholipase A2 activity
calcium ion binding
calcium-dependent phospholipid binding
phospholipase A1 activity

Cellular Component

nucleus
cytoplasm
mitochondrial inner membrane
endoplasmic reticulum
endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367466
Coding exons: 17
Length: 160029
Individuals with no LoFs: 125719
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 125748
p: 0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.35	265	397	0.667	0.0000198	5027
Missense (PolyPhen)		66	151.3	0.43621		1950
Synonymous	-0.0493	137	136	1.01	0.00000724	1338
Loss of Function	3.53	14	37.3	0.376	0.00000195	464

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	0.00011	0.00011	rare
Finnish	0.00037	0.00037	rare
European (Non-Finnish)	0.000071	0.000070	rare
South Asian	0.00026	0.00026	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Selectively hydrolyzes arachidonyl phospholipids in the sn-2 position releasing arachidonic acid. Together with its lysophospholipid activity, it is implicated in the initiation of the inflammatory response.;
Disease: DISEASE: Note=PLA2G4A mutations resulting in phospholipase A2 deficiency have been found in a patient affected by recurrent episodes of multiple complicated ulcers of the small intestine, not due to cyclooxygenase inhibitors use. Disease features also include platelet dysfunction, and globally decreased eicosanoid synthesis (PubMed:18451993). {ECO:0000269|PubMed:18451993}.;

Recessive Scores

pRec: 0.448

Intolerance Scores

LoFtool: 0.642
RVIS EVS: -0.25
RVIS percentile EVS: 35.99

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.945

Gene Damage Prediction

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