PGAP1

protein-coding

post-GPI attachment to proteins inositol deacylase 1

Gene summary

The protein encoded by this gene functions early in the glycosylphosphatidylinositol (GPI) biosynthetic pathway, catalyzing the inositol deacylation of GPI. The encoded protein is required for the production of GPI that can attach to proteins, and this may be an important factor in the transport of GPI-anchored proteins from the endoplasmic reticulum to the Golgi. Defects in this gene are a cause an autosomal recessive form of cognitive impairment. [provided by RefSeq, Jul 2017]

MANE transcript

NM_024989.4

Inheritance

ClinVar variants

P:45U:193B:90

Top phenotype

Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr2:196,833,004-196,927,796

External References & Databases

Ensembl (ENSG00000197121)

Transcript & Mutation Effects

hg38 • Region Span ~94.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive spastic paraplegia type 67SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018419

Submitter: Orphanet

intellectual disability, autosomal recessive 42STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014348

Submitter: Labcorp Genetics (formerly Invitae)

intellectual disability, autosomal recessive 42STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014348

Submitter: G2P

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

intellectual disability, autosomal recessive 42STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014348

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalitiesAR

Manifestation: Craniofacial; 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: 24784135

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PGAP1 variants in ClinVar

12 Conditions Cataloged

Intellectual disability, autosomal recessive 42Total: 303

Inborn genetic diseasesTotal: 110

not providedTotal: 79

not specifiedTotal: 29

Hereditary spastic paraplegiaTotal: 29

PGAP1-related disorderTotal: 8

See casesTotal: 3

Neurodevelopmental disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024989.4. 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	3 clinvar	71 clinvar	3 clinvar	78
missense			183 clinvar	16 clinvar		199
nonsense	6 clinvar	11 clinvar				17
start loss						0
frameshift	9 clinvar	4 clinvar	2 clinvar			15
splice donor/acceptor (+/-2bp)	6 clinvar	8 clinvar	5 clinvar			19
Total	21	24	193	87	3	328

Highest pathogenic variant AF is 0.000017355129

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024989.4	RefSeq	NP_079265.2	27	MANE Select
ENST00000354764.9	Ensembl	ENSP00000346809.3	27	MANE Select
NM_001321099.2	RefSeq	NP_001308028.1	24	Standard
NM_001321100.2	RefSeq	NP_001308029.1	18	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pgap1	Danio rerio	Structure: ceratobranchial cartilage Quality: shortened abnormal

Gene / Model

Organism

Observed Phenotype

pgap1

Danio rerio

Structure: ceratobranchial cartilage

Quality: shortened

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycosylphosphatidylinositol (GPI)-anchor biosynthesis - Homo sapiens (human)
Attachment of GPI anchor to uPAR
Post-translational modification: synthesis of GPI-anchored proteins
Post-translational protein modification
Metabolism of proteins

Biological Process

GPI anchor metabolic process
endoplasmic reticulum to Golgi vesicle-mediated transport
sensory perception of sound
embryonic pattern specification
anterior/posterior axis specification

Molecular Function

nuclease activity
hydrolase activity, acting on ester bonds
phosphoric ester hydrolase activity
phosphatidylinositol deacylase activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000354764
Coding exons: 27
Length: 94793
Individuals with no LoFs: 125689
Homozygous LoFs: 0
Heterozygous LoFs: 59
Defined: 125748
p: 0.000235

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.26	379	455	0.834	0.0000221	5990
Missense (PolyPhen)		95	131.68	0.72145		1727
Synonymous	0.799	146	159	0.919	0.00000778	1729
Loss of Function	3.89	22	52.4	0.420	0.00000244	711

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00026	0.00025	rare
Latino/Admixed American	0.00020	0.00017	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.00028	0.00027	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00023	0.00023	rare
South Asian	0.00025	0.00020	rare
Other	0.00052	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in inositol deacylation of GPI-anchored proteins. GPI inositol deacylation may important for efficient transport of GPI-anchored proteins from the endoplasmic reticulum to the Golgi (By similarity). {ECO:0000250}.;
Disease: DISEASE: Mental retardation, autosomal recessive 42 (MRT42) [MIM:615802]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:24482476, ECO:0000269|PubMed:24784135}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.219
RVIS EVS: -0.67
RVIS percentile EVS: 15.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.334

Gene Damage Prediction

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