PIGM

protein-coding

phosphatidylinositol glycan anchor biosynthesis class M, the group of Dolichyl D-mannosyl phosphate dependent mannosyltransferases|Phosphatidylinositol glycan anchor biosynthesis

Gene summary

This gene encodes a transmembrane protein that is located in the endoplasmic reticulum and is involved in GPI-anchor biosynthesis. The glycosylphosphatidylinositol (GPI)-anchor is a glycolipid which contains three mannose molecules in its core backbone. The GPI-anchor is found on many blood cells and serves to anchor proteins to the cell surface. This gene encodes a mannosyltransferase, GPI-MT-I, that transfers the first mannose to GPI on the lumenal side of the endoplasmic reticulum. [provided by RefSeq, Jul 2008]

MANE transcript

NM_145167.3

Inheritance

ClinVar variants

P:3U:130B:20

Top phenotype

Glycosylphosphatidylinositol biosynthesis defect 1

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr1:160,024,953-160,031,990

External References & Databases

Ensembl (ENSG00000143315)

Transcript & Mutation Effects

hg38 • Region Span ~7.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypercoagulability syndrome due to glycosylphosphatidylinositol deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012465

Submitter: G2P

congenital disorder of glycosylationLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0015286

Submitter: ClinGen

*PIGM* was first reported in relation to autosomal recessive congenital disorder of glycosylation (also known as hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency) in 2006 (Almeida et al., PMID 16767100). Two variants (promoter, missense) that have been reported in 6 probands in 4 publications (PMIDs 16767100, 31445883, 39119839, 39425582) are included in this curation. Patients have a range of symptoms, including macrocephaly, hepatosplenomegaly, cytopenias, and portal vein thrombosis. The disease mechanism appears to be biallelic loss of function. Heterozygous carriers are reportedly unaffected. This gene-disease relationship is also supported by in vitro and in vivo assays showing a deficiency in glycosylphosphatidylinositol (GPI) biosynthesis (PMIDs 11226175, 16767100). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on February 6th, 2025 (SOP Version 11).

hypercoagulability syndrome due to glycosylphosphatidylinositol deficiencyLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012465

Submitter: Labcorp Genetics (formerly Invitae)

hypercoagulability syndrome due to glycosylphosphatidylinositol deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012465

Submitter: Orphanet

hypercoagulability syndrome due to glycosylphosphatidylinositol deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012465

Submitter: PanelApp Australia

hypercoagulability syndrome due to glycosylphosphatidylinositol deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012465

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Glycosylphosphatidylinositol biosynthesis defect 1AR

Manifestation: Biochemical; Hematologic; Neurologic

Intervention: Biochemical; Hematologic; Neurologic; Pharmacogenomic

Rationale: Medical treatment may be beneficial (eg, prophylactic oral anticoagulants to prevent thrombosis; sodium phenylbutyrate for seizure control); Awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery; Hepatic-metabolized agents should be avoided

Refs: 16767100; 17442906; 19168132; 31445883

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIGM variants in ClinVar

6 Conditions Cataloged

Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiencyTotal: 98

not specifiedTotal: 71

not providedTotal: 19

PIGM-related disorderTotal: 8

Inborn genetic diseasesTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_145167.3. 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			6 clinvar	15 clinvar	3 clinvar	24
missense			118 clinvar		2 clinvar	120
nonsense		1 clinvar	1 clinvar			2
start loss		1 clinvar				1
frameshift	1 clinvar		5 clinvar			6
splice donor/acceptor (+/-2bp)						0
Total	1	2	130	15	5	153

Highest pathogenic variant AF is 0.000029120054

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_145167.3	RefSeq	NP_660150.1	1	MANE Select
ENST00000368090.5	Ensembl	ENSP00000357069.2	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

GPI anchor biosynthetic process

Molecular Function

transferase activity, transferring hexosyl groups

Cellular Component

endoplasmic reticulum membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368090
Coding exons: 1
Length: 4322
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0811	215	212	1.02	0.0000103	2735
Missense (PolyPhen)		72	79.781	0.90247		1063
Synonymous	0.0922	90	91.1	0.988	0.00000463	893
Loss of Function	0.957	8	11.5	0.695	5.05e-7	146

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mannosyltransferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers the first alpha-1,4-mannose to GlcN-acyl-PI during GPI precursor assembly. {ECO:0000269|PubMed:11226175}.;
Disease: DISEASE: Glycosylphosphatidylinositol deficiency (GPID) [MIM:610293]: Autosomal recessive trait that results in a propensity to venous thrombosis and seizures. Deficiency is due to a point mutation in the regulatory sequences of PIGM that disrupts binding of the transcription factor SP1 to its cognate promoter motif, leading to a strong reduction of expression. {ECO:0000269|PubMed:16767100}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.102

Intolerance Scores

LoFtool: 0.675
RVIS EVS: -0.27
RVIS percentile EVS: 34.6

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.371

Gene Damage Prediction

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