rs587777396

Variant names:

• chrX-15331576-G-A
• rs587777396
• NM_002641.4:c.355C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001451531: 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).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R119Q) has been classified 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:5
• Conservation: PhyloP100: 4.94
• Publications: 9 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):

• complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• multiple congenital anomalies-hypotonia-seizures syndrome 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001451531: 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).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_002641.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-15331575-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 813740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 132814.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGA	NM_002641.4	MANE Select	c.355C>T	p.Arg119Trp	missense	Exon 2 of 6	NP_002632.1	P37287-1
	PIGA	NM_001440789.1		c.355C>T	p.Arg119Trp	missense	Exon 2 of 7	NP_001427718.1
	PIGA	NM_001440790.1		c.14-3263C>T		intron	N/A	NP_001427719.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGA	ENST00000333590.6	TSL:1 MANE Select	c.355C>T	p.Arg119Trp	missense	Exon 2 of 6	ENSP00000369820.3	P37287-1
	PIGA	ENST00000542278.6	TSL:5	c.355C>T	p.Arg119Trp	missense	Exon 2 of 6	ENSP00000442653.2	P37287-1
	PIGA	ENST00000635543.1	TSL:4	c.355C>T	p.Arg119Trp	missense	Exon 2 of 2	ENSP00000489205.1	A0A0U1RQW8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Multiple congenital anomalies-hypotonia-seizures syndrome 2 (3)
1	-	-	not provided (1)
1	-	-	Paroxysmal nocturnal hemoglobinuria 1 (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		4.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.83		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
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777396; hg19: chrX-15349698;