rs587777396

Positions:

• chrX-15331576-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_002641.4(PIGA):​c.355C>T​(p.Arg119Trp) variant causes a missense change. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PIGA NM_002641.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.94

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant X-15331576-G-A is Pathogenic according to our data. Variant chrX-15331576-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 132814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-15331576-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGA	NM_002641.4	c.355C>T	p.Arg119Trp	missense_variant	2/6	ENST00000333590.6	NP_002632.1
PIGA	NM_020473.3	c.13+3925C>T		intron_variant			NP_065206.3
PIGA	NR_033835.1	n.457+14C>T		intron_variant, non_coding_transcript_variant
PIGA	NR_033836.1	n.173+298C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGA	ENST00000333590.6	c.355C>T	p.Arg119Trp	missense_variant	2/6	1	NM_002641.4	ENSP00000369820	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Oct 12, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 06, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 16, 2019	The PIGA c.355C>T (p.Arg119Trp) variant is a missense variant that has been reported in a hemizygous state in one male who presented with facial dysmorphisms, thin corpus callosum, delayed myelination, early onset epilepsy, hypotonia and profound intellectual disability and in a heterozygous state in the individual's unaffected mother (Kato et al. 2014). Another affected male individual was found to be hemizygous for a different variant at the same amino acid residue, c.356G>A (p.Arg119Gln), and presented with similar features (Lin et al. 2018). The p.Arg119Trp variant is absent from the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Functional impact of the variant was assessed by examining the surface expression of three different GPI-anchored proteins, FLAER, CD24 and CD16, in patient granulocytes by flow cytometry. The authors found decreased expression of at least two proteins, CD24 and CD16, as compared to normal controls (Kato et al. 2014). In addition, several in-silico tools predict the Arg119Trp change to be deleterious. Based on the collective evidence and application of the ACMG criteria, the p.Arg119Trp variant is classified as likely pathogenic for multiple congenital anomalies-hypotonia-seizures syndrome 2. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2023

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24706016, 26923721, 32452540, 31175295, 29502866, 29656098) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;D;.
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.4	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.2	D;.;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.92
MutPred		0.83		Loss of methylation at R114 (P = 0.049);Loss of methylation at R114 (P = 0.049);Loss of methylation at R114 (P = 0.049);
MVP		0.97
MPC		1.6
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587777396; hg19: chrX-15349698;