X-15321592-C-T

Variant names:

• chrX-15321592-C-T
• rs1440750558
• NM_002641.4:c.1369G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_002641.4(PIGA):​c.1369G>A​(p.Ala457Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PIGA NM_002641.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.32
• Publications: 0 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 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 3 uncertain in NM_002641.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31349853).

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.1369G>A	p.Ala457Thr	missense	Exon 6 of 6	NP_002632.1
	PIGA	NM_001440789.1		c.1462G>A	p.Ala488Thr	missense	Exon 7 of 7	NP_001427718.1
	PIGA	NM_001440790.1		c.760G>A	p.Ala254Thr	missense	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.1369G>A	p.Ala457Thr	missense	Exon 6 of 6	ENSP00000369820.3
	PIGA	ENST00000542278.6	TSL:5	c.1369G>A	p.Ala457Thr	missense	Exon 6 of 6	ENSP00000442653.2
	PIGA	ENST00000482148.6	TSL:5	c.862G>A	p.Ala288Thr	missense	Exon 5 of 5	ENSP00000489528.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 2 Uncertain:2

Oct 11, 2019

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The hemizygous p.Ala457Thr variant identified in the PIGA gene has not been reported in the medical literature and it is absent from gnomAD database. In silico prediction tools show conflicting predictions about its pathogenicity. Based on the available evidence, the p.Ala457Thr variant in the PIGA gene is assessed as variant of uncertain significance.

Jan 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PIGA-related conditions. ClinVar contains an entry for this variant (Variation ID: 539320). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 457 of the PIGA protein (p.Ala457Thr).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.13
Sift	Benign	0.38	T
Sift4G	Benign	0.39	T
Polyphen		1.0	D
Vest4		0.41
MutPred		0.32		Gain of relative solvent accessibility (P = 0.0023)
MVP		0.71
MPC		0.62
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.28
gMVP		0.89
Mutation Taster		=49/51	disease causing

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: rs1440750558; hg19: chrX-15339714;