PGAP3

protein-coding

post-GPI attachment to proteins phospholipase 3

Gene summary

This gene encodes a glycosylphosphatidylinositol (GPI)-specific phospholipase that primarily localizes to the Golgi apparatus. This ubiquitously expressed gene is predicted to encode a seven-transmembrane protein that removes unsaturated fatty acids from the sn-2 position of GPI. The remodeling of the constituent fatty acids on GPI is thought to be important for the proper association between GPI-anchored proteins and lipid rafts. The tethering of proteins to plasma membranes via posttranslational GPI-anchoring is thought to play a role in protein sorting and trafficking. Mutations in this gene cause an autosomal recessive form of neurologic hyperphosphatasia with cognitive disability (HPMRS4). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

Previous symbols:

PERLD1

MANE transcript

NM_033419.5

Inheritance

ClinVar variants

P:44U:86B:70

Top phenotype

Hyperphosphatasia with impaired intellectual development syndrome 4

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr17:39,671,122-39,696,797

External References & Databases

Ensembl (ENSG00000161395)

Transcript & Mutation Effects

hg38 • Region Span ~25.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperphosphatasia with impaired intellectual development syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014318

Submitter: Labcorp Genetics (formerly Invitae)

hyperphosphatasia-intellectual disability syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016596

Submitter: Orphanet

hyperphosphatasia with impaired intellectual development syndrome 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014318

Submitter: G2P

hyperphosphatasia with impaired intellectual development syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014318

Submitter: PanelApp Australia

hyperphosphatasia with impaired intellectual development syndrome 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014318

Submitter: ClinGen

*PGAP3* was first reported in relation to autosomal recessive hyperphosphatasia with intellectual disability syndrome 4 in 2014 (Howard et al., PMID: 24439110). Common phenotypes in individuals with *PGAP3* pathogenic variants include severe global developmental delay, speech and language delay, intellectual disability, hypotonia, ataxia, seizures, distinct facial abnormalities (including broad nasal bridge and tip, short nose, long palpebral fissures, hypertelorism, long philtrum, thin and wide upper lip, large ear lobes, and full cheeks), autistic behaviour, and sleep disturbances. Additionally, some patients exhibit cleft palate and microcephaly, decreased intrauterine fetal movements, cardiac problems, abnormal corpus callosum, and olfactory bulb agenesis. Nineteen homozygous and compound heterozygous variants (13 missense, 1 splicing, 2 frameshift, 2 nonsense, and 1 UTR) that have been reported in seven publications (PMIDs: 24439110, 27120253, 29531774, 30217754, 30345601, 32726939, 32845056) are included in this curation. The presumed mechanism of pathogenicity is loss of function, whereby variants in *PGAP3* lead to a reduction in functional GPI-anchored proteins. This gene-disease relationship is also supported by a zebrafish model and protein interaction data (Da'as et al., 2020, PMID: 32726939; Castillon et al., 2013, PMID: 23615438). In summary, there is definitive evidence supporting the relationship between *PGAP3* and autosomal recessive hyperphosphatasia with intellectual disability syndrome 4. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 5, 2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Hyperphosphatasia with impaired intellectual development syndrome 4AR

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 22315194; 24439110; 29620724; 30217754; 30345601

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PGAP3 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 158

Inborn genetic diseasesTotal: 56

Hyperphosphatasia with intellectual disability syndrome 4Total: 44

PGAP3-related disorderTotal: 11

not specifiedTotal: 2

Hyperphosphatasia-intellectual disability syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_033419.5. 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	56 clinvar	1 clinvar	58
missense	6 clinvar	9 clinvar	84 clinvar	12 clinvar	1 clinvar	112
nonsense	8 clinvar	3 clinvar				11
start loss						0
frameshift	8 clinvar	5 clinvar				13
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	1 clinvar			6
Total	24	20	86	68	2	200

Highest pathogenic variant AF is 0.00040987978

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_033419.5	RefSeq	NP_219487.3	8	MANE Select
ENST00000300658.9	Ensembl	ENSP00000300658.4	8	MANE Select
NM_001291726.2	RefSeq	NP_001278655.1	7	Standard
NM_001291728.2	RefSeq	NP_001278657.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

GPI anchor metabolic process
GPI anchor biosynthetic process

Molecular Function

hydrolase activity, acting on ester bonds

Cellular Component

Golgi membrane
integral component of membrane
intrinsic component of endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000300658
Coding exons: 8
Length: 25676
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 125748
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.685	154	180	0.856	0.0000109	2019
Missense (PolyPhen)		53	59.847	0.88559		748
Synonymous	0.671	73	80.7	0.905	0.00000514	650
Loss of Function	2.05	7	15.8	0.444	6.77e-7	167

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	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000046	0.000044	rare
South Asian	0.000065	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the lipid remodeling steps of GPI-anchor maturation. Lipid remodeling steps consist in the generation of 2 saturated fatty chains at the sn-2 position of GPI-anchors proteins. Required for phospholipase A2 activity that removes an acyl-chain at the sn-2 position of GPI-anchors during the remodeling of GPI (Probable). {ECO:0000305|PubMed:17021251}.;

Recessive Scores

pRec: 0.132

Intolerance Scores

LoFtool: 0.177
RVIS EVS: 0.33
RVIS percentile EVS: 73.41

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.339

Gene Damage Prediction

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