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_001440789.1(PIGA):​c.1123_1125delCTT​(p.Leu375del) 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_001440789.1 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_001440789.1. 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440789.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGA	NM_002641.4	MANE Select	c.1030_1032delCTT	p.Leu344del	conservative_inframe_deletion	Exon 5 of 6	NP_002632.1
	PIGA	NM_001440789.1		c.1123_1125delCTT	p.Leu375del	conservative_inframe_deletion	Exon 6 of 7	NP_001427718.1
	PIGA	NM_001440790.1		c.421_423delCTT	p.Leu141del	conservative_inframe_deletion	Exon 5 of 6	NP_001427719.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGA	ENST00000333590.6	TSL:1 MANE Select	c.1030_1032delCTT	p.Leu344del	conservative_inframe_deletion	Exon 5 of 6	ENSP00000369820.3
	PIGA	ENST00000475746.1	TSL:1	c.81+197_81+199delCTT		intron	N/A	ENSP00000488970.1
	PIGA	ENST00000542278.6	TSL:5	c.1030_1032delCTT	p.Leu344del	conservative_inframe_deletion	Exon 5 of 6	ENSP00000442653.2

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

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Multiple congenital anomalies-hypotonia-seizures syndrome 2 (1)
1	-	-	Neurodevelopmental disorder with epilepsy and hemochromatosis (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;