PIGA

phosphatidylinositol glycan anchor biosynthesis class A, the group of Phosphatidylinositol glycan anchor biosynthesis|Glycosylphosphatidylinositol-N-acetylglucosaminyltransferase complex|Glycosyl transferases group 1 domain containing

Basic information

Region (hg38): X:15319452-15335554

Links

ENSG00000165195 ∙ NCBI:5277 ∙ OMIM:311770 ∙ HGNC:8957 ∙ Uniprot:P37287 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• infantile spasms (Supportive), mode of inheritance: AD
• malignant migrating partial seizures of infancy (Supportive), mode of inheritance: AD
• multiple congenital anomalies-hypotonia-seizures syndrome 2 (Supportive), mode of inheritance: XL
• ferro-cerebro-cutaneous syndrome (Supportive), mode of inheritance: XL
• multiple congenital anomalies-hypotonia-seizures syndrome 2 (Strong), mode of inheritance: XL
• multiple congenital anomalies-hypotonia-seizures syndrome 2 (Moderate), mode of inheritance: XL
• multiple congenital anomalies-hypotonia-seizures syndrome 2 (Definitive), mode of inheritance: XL
• paroxysmal nocturnal hemoglobinuria (Supportive), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Multiple congenital anomalies-hypotonia-seizures syndrome 2; Neurodevelopmental disorder with epilepsy and hemochromatosis	XL	Cardiovascular; Gastrointestinal; Hematologic	Multiple congenital anomalies-hypotonia-seizures syndrome 2 can involve congenital cardiac anomalies, and awareness may allow early management; Neurodevelopmental disorder with epilepsy and hemochromatosis can involve early-onset iron overload, and awareness may allow more precise management	Cardiovascular; Craniofacial; Dermatologic; Gastrointestinal; Genitourinary; Hematologic; Neurologic	22305531; 24259288; 33632934; 34875027
The condition can involve multiple congenital anomalies

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PIGA gene.

• Multiple_congenital_anomalies-hypotonia-seizures_syndrome_2 (257 variants)
• not_provided (109 variants)
• Inborn_genetic_diseases (35 variants)
• Paroxysmal_nocturnal_hemoglobinuria_1 (19 variants)
• not_specified (17 variants)
• PIGA-related_disorder (16 variants)
• Paroxysmal_nocturnal_hemoglobinuria (10 variants)
• Neurodevelopmental_disorder_with_epilepsy_and_hemochromatosis (7 variants)
• Intellectual_disability (3 variants)
• Epileptic_encephalopathy (1 variants)
• Neurodevelopmental_abnormality (1 variants)
• See_cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PIGA gene is commonly pathogenic or not. These statistics are base on transcript: NM_000002641.4. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				63	2	65
missense	6	24	148	22	8	208
nonsense	3	1				4
start loss		1				1
frameshift	9	7	1			17
splice donor/acceptor (+/-2bp)	2	3				5
Total	20	36	149	85	10

Highest pathogenic variant AF is 0.00000247817

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PIGA	protein_coding	protein_coding	ENST00000333590	5	16104

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.961	0.0392	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.17	105	189	0.556	0.0000143	3169
Missense in Polyphen		14	74.454	0.18804		1266
Synonymous	1.61	51	67.8	0.752	0.00000508	988
Loss of Function	2.95	0	10.1	0.00	7.74e-7	205

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Necessary for the synthesis of N-acetylglucosaminyl- phosphatidylinositol, the very early intermediate in GPI-anchor biosynthesis.
• Disease: DISEASE: Paroxysmal nocturnal hemoglobinuria 1 (PNH1) [MIM:300818]: A disorder characterized by hemolytic anemia with hemoglobinuria, thromboses in large vessels, and a deficiency in hematopoiesis. Red blood cell breakdown with release of hemoglobin into the urine is manifested most prominently by dark-colored urine in the morning. {ECO:0000269|PubMed:10087994, ECO:0000269|PubMed:12037021, ECO:0000269|PubMed:8167330, ECO:0000269|PubMed:8306954, ECO:0000269|PubMed:8500164}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) [MIM:300868]: An X-linked recessive developmental disorder characterized by dysmorphic features, neonatal hypotonia, myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems. Most affected individuals die in infancy. {ECO:0000269|PubMed:22305531, ECO:0000269|PubMed:24259184, ECO:0000269|PubMed:24259288, ECO:0000269|PubMed:24706016, ECO:0000269|PubMed:26993267}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: 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;Phosphatidylinositol phosphate metabolism (Consensus)

Recessive Scores

• pRec: 0.226

Intolerance Scores

• rvis_EVS: 0.24
• rvis_percentile_EVS: 68.98

Haploinsufficiency Scores

• pHI: 0.123
• hipred: Y
• hipred_score: 0.628
• ghis: 0.410

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.676

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Piga
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; neoplasm; reproductive system phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; growth/size/body region phenotype; craniofacial phenotype; cellular phenotype

Gene ontology

• Biological process: GPI anchor biosynthetic process;positive regulation of metabolic process;preassembly of GPI anchor in ER membrane;cellular response to leukemia inhibitory factor
• Cellular component: glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex;endoplasmic reticulum membrane;membrane;integral component of membrane
• Molecular function: protein binding;UDP-glycosyltransferase activity;phosphatidylinositol N-acetylglucosaminyltransferase activity