rs387906726

chrX-15321727-G-AchrX-15321727-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_002641.4(PIGA):c.1234C>T(p.Arg412Ter) 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 6 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 id is 29988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-15321727-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGA	NM_002641.4	c.1234C>T	p.Arg412Ter	stop_gained	6/6	ENST00000333590.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGA	ENST00000333590.6	c.1234C>T	p.Arg412Ter	stop_gained	6/6	1	NM_002641.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

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

Pathogenic, no assertion criteria provided	literature only	OMIM	May 06, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects PIGA function (PMID: 22305531, 28441409). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 29988). This premature translational stop signal has been observed in individuals with PIGA-related multiple congenital anomalies-hypotonia-seizures syndrome (PMID: 22305531, 24706016, 26545172). This variant is not present in population databases (gnomAD no frequency). 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. -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Feb 05, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2020	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 v4.3

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
MutationTaster	Benign	1.0	D;D;D
Vest4		0.77
GERP RS		3.9

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906726; hg19: chrX-15339849; COSMIC: COSV61236744; COSMIC: COSV61236744;