PGAP2

protein-coding

post-GPI attachment to proteins 2

Gene summary

The protein encoded by this gene plays a role in the maturation of glycosylphosphatidylinositol (GPI) anchors on GPI-anchored proteins. Mutations in this gene are associated with an autosomal recessive syndrome characterized by hyperphosphatasia and intellectual disability. [provided by RefSeq, Jul 2017]

Previous symbols:

MRT21
MRT17

MANE transcript

NM_014489.4

Inheritance

ClinVar variants

P:21U:64B:26

Top phenotype

Hyperphosphatasia with impaired intellectual development syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr11:3,797,724-3,826,371

External References & Databases

Ensembl (ENSG00000148985)

Transcript & Mutation Effects

hg38 • Region Span ~28.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperphosphatasia with impaired intellectual development syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013628

Submitter: Labcorp Genetics (formerly Invitae)

hyperphosphatasia-intellectual disability syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016596

Submitter: Orphanet

hyperphosphatasia with impaired intellectual development syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013628

Submitter: PanelApp Australia

hyperphosphatasia with impaired intellectual development syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013628

Submitter: G2P

Clinical Genomic Database (CGD)

Hyperphosphatasia with impaired intellectual development syndrome 3AR

Manifestation: 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: 21629298; 21643797; 23561846; 23561847

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PGAP2 variants in ClinVar

11 Conditions Cataloged

Inborn genetic diseasesTotal: 52

not providedTotal: 48

Hyperphosphatasia with intellectual disability syndrome 3Total: 31

Hyperphosphatasia with intellectual disability syndrome 1Total: 2

PGAP2-related disorderTotal: 2

Autism spectrum disorderTotal: 2

MicrognathiaTotal: 1

Congenital omphaloceleTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014489.4. 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			3 clinvar	18 clinvar	1 clinvar	22
missense	3 clinvar	11 clinvar	57 clinvar	7 clinvar		78
nonsense	1 clinvar		1 clinvar			2
start loss	1 clinvar	1 clinvar				2
frameshift	1 clinvar	2 clinvar	2 clinvar			5
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar			2
Total	6	15	64	25	1	111

Highest pathogenic variant AF is 0.00030420333

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 114 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014489.4	RefSeq	NP_055304.1	6	MANE Select
ENST00000278243.9	Ensembl	ENSP00000278243.4	6	MANE Select
NM_001145438.3	RefSeq	NP_001138910.2	5	Standard
NM_001256235.2	RefSeq	NP_001243164.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

GPI anchor biosynthetic process
protein transport

Molecular Function

protein binding
protein transporter activity

Cellular Component

Golgi membrane
endoplasmic reticulum membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000278243
Coding exons: 6
Length: 28648
Individuals with no LoFs: 125668
Homozygous LoFs: 0
Heterozygous LoFs: 80
Defined: 125748
p: 0.000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.933	168	206	0.817	0.0000138	2058
Missense (PolyPhen)		51	66.192	0.77049		688
Synonymous	-0.211	91	88.5	1.03	0.00000634	632
Loss of Function	3.09	1	13.1	0.0765	5.59e-7	147

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.00055	0.00055	rare
European (Non-Finnish)	0.00052	0.00052	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the lipid remodeling steps of GPI-anchor maturation. Required for stable expression of GPI-anchored proteins at the cell surface (By similarity). {ECO:0000250}.;

Intolerance Scores

LoFtool: 0.327
RVIS EVS: -0.29
RVIS percentile EVS: 33.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.457