rs587777399

Variant names:

• chrX-15324820-TAAG-T
• rs587777399
• NM_002641.4:c.1030_1032delCTT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP5_Moderate

The NM_002641.4(PIGA):​c.1030_1032delCTT​(p.Leu344del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PIGA NM_002641.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 8.63
• Publications: 3 publications found

Genes affected

PIGA (HGNC:8957): (phosphatidylinositol glycan anchor biosynthesis class A) This gene encodes a protein required for synthesis of N-acetylglucosaminyl phosphatidylinositol (GlcNAc-PI), the first intermediate in the biosynthetic pathway of GPI anchor. The GPI anchor is a glycolipid found on many blood cells and which serves to anchor proteins to the cell surface. Paroxysmal nocturnal hemoglobinuria, an acquired hematologic disorder, has been shown to result from mutations in this gene. Alternate splice variants have been characterized. A related pseudogene is located on chromosome 12. [provided by RefSeq, Jun 2010]

PIGA Gene-Disease associations (from GenCC):

• multiple congenital anomalies-hypotonia-seizures syndrome 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae), Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ferro-cerebro-cutaneous syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal nocturnal hemoglobinuria

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_002641.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant X-15324820-TAAG-T is Pathogenic according to our data. Variant chrX-15324820-TAAG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 132818.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGA	NM_002641.4	c.1030_1032delCTT	p.Leu344del	conservative_inframe_deletion	Exon 5 of 6	ENST00000333590.6	NP_002632.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGA	ENST00000333590.6	c.1030_1032delCTT	p.Leu344del	conservative_inframe_deletion	Exon 5 of 6	1	NM_002641.4	ENSP00000369820.3

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 2 Pathogenic:1

Sep 08, 2002

Center of Excellence for Medical Genomics, Chulalongkorn University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

May 13, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1030_1032delCTT pathogenic variant in the PIGA gene has been reported previously in a multi-generationalfamily with three affected males with neurodegeneration, cutaneous abnormalities and systemic iron overload(Swoboda et al., 2014). Analysis of blood cells from an affected individual showed deficient GPI anchor proteins ingranulocytes but not erythrocytes or monocytes, suggesting a cell-type dependent reduction of PIGA activity due tothis variant (Swoboda et al., 2014). The c.1030_1032delCTT variant causes an in-frame deletion of codon Leucine344, denoted p.L344del. The Leucine 344 residue is conserved across species. The c.1030_1032delCTT variant wasnot observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. We interpretc.1030_1032delCTT as a pathogenic variant. -

Neurodevelopmental disorder with epilepsy and hemochromatosis Pathogenic:1

Jan 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.6
Mutation Taster		=54/46	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777399; hg19: chrX-15342942;