rs387906726

Variant names:

• chrX-15321727-G-A
• rs387906726
• NM_002641.4:c.1234C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-15321727-G-A
• chrX-15321727-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_002641.4(PIGA):​c.1234C>T​(p.Arg412*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R412R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PIGA NM_002641.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.15
• Publications: 14 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: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-15321727-G-A is Pathogenic according to our data. Variant chrX-15321727-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 29988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002641.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGA	NM_002641.4	MANE Select	c.1234C>T	p.Arg412*	stop_gained	Exon 6 of 6	NP_002632.1
	PIGA	NM_001440789.1		c.1327C>T	p.Arg443*	stop_gained	Exon 7 of 7	NP_001427718.1
	PIGA	NM_001440790.1		c.625C>T	p.Arg209*	stop_gained	Exon 6 of 6	NP_001427719.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGA	ENST00000333590.6	TSL:1 MANE Select	c.1234C>T	p.Arg412*	stop_gained	Exon 6 of 6	ENSP00000369820.3
	PIGA	ENST00000475746.1	TSL:1	c.127C>T	p.Arg43*	stop_gained	Exon 2 of 2	ENSP00000488970.1
	PIGA	ENST00000542278.6	TSL:5	c.1234C>T	p.Arg412*	stop_gained	Exon 6 of 6	ENSP00000442653.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 2 Pathogenic:3

Feb 05, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 06, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg412*) in the PIGA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acid(s) of the PIGA protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with PIGA-related multiple congenital anomalies-hypotonia-seizures syndrome (PMID: 22305531, 24706016, 26545172). ClinVar contains an entry for this variant (Variation ID: 29988). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PIGA function (PMID: 22305531, 28441409). For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:2

Jun 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 02, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 73 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23561846, 24784135, 22305531, 32562213, 28441409, 24706016, 26545172, 31704190, 32256299)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		2.1
Vest4		0.77
GERP RS		3.9
Mutation Taster		=7/193	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs387906726; hg19: chrX-15339849; COSMIC: COSV61236744; COSMIC: COSV61236744;