rs1555945533

Variant names:

• chrX-15331819-C-T
• rs1555945533
• NM_002641.4:c.112G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_002641.4(PIGA):​c.112G>A​(p.Val38Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,097,872 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V38A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: PIGA NM_002641.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49
• 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):

• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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-15331818-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 390052.Status of the report is criteria_provided_single_submitter, 1 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.112G>A	p.Val38Ile	missense	Exon 2 of 6	NP_002632.1	P37287-1
	PIGA	NM_001440789.1		c.112G>A	p.Val38Ile	missense	Exon 2 of 7	NP_001427718.1
	PIGA	NM_001440790.1		c.14-3506G>A		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.112G>A	p.Val38Ile	missense	Exon 2 of 6	ENSP00000369820.3	P37287-1
	PIGA	ENST00000542278.6	TSL:5	c.112G>A	p.Val38Ile	missense	Exon 2 of 6	ENSP00000442653.2	P37287-1
	PIGA	ENST00000482148.6	TSL:5	c.112G>A	p.Val38Ile	missense	Exon 2 of 5	ENSP00000489528.1	P37287-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097872 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363234

African (AFR) AF: 0.00 AC: 0 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841795

Other (OTH) AF: 0.00 AC: 0 AN: 46085

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Multiple congenital anomalies-hypotonia-seizures syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.33
Sift	Benign	0.090	T
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.48
MutPred		0.61		Loss of catalytic residue at V38 (P = 0.0429)
MVP		0.76
MPC		1.0
ClinPred		0.81	D
GERP RS		6.1
Varity_R		0.15
gMVP		0.62
Mutation Taster		=27/73	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: rs1555945533; hg19: chrX-15349941;