X-15321543-C-T

Variant names:

• chrX-15321543-C-T
• rs773189052
• NM_002641.4:c.1418G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002641.4(PIGA):​c.1418G>A​(p.Arg473Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 112,429 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R473T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
• Consequence: PIGA NM_002641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• 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, Labcorp Genetics (formerly Invitae), G2P
• 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029266715).

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.1418G>A	p.Arg473Lys	missense	Exon 6 of 6	NP_002632.1	P37287-1
	PIGA	NM_001440789.1		c.1511G>A	p.Arg504Lys	missense	Exon 7 of 7	NP_001427718.1
	PIGA	NM_001440790.1		c.809G>A	p.Arg270Lys	missense	Exon 6 of 6	NP_001427719.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGA	ENST00000333590.6	TSL:1 MANE Select	c.1418G>A	p.Arg473Lys	missense	Exon 6 of 6	ENSP00000369820.3	P37287-1
	PIGA	ENST00000542278.6	TSL:5	c.1418G>A	p.Arg473Lys	missense	Exon 6 of 6	ENSP00000442653.2	P37287-1
	PIGA	ENST00000482148.6	TSL:5	c.911G>A	p.Arg304Lys	missense	Exon 5 of 5	ENSP00000489528.1	P37287-2

Frequencies

GnomAD3 genomes AF: 0.00000889 AC: 1 AN: 112429 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome AF: 0.00000889 AC: 1 AN: 112429 Hom.: 0 Cov.: 23 AF XY: 0.0000289 AC XY: 1 AN XY: 34589

African (AFR) AF: 0.00 AC: 0 AN: 30917

American (AMR) AF: 0.00 AC: 0 AN: 10570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3616

South Asian (SAS) AF: 0.00 AC: 0 AN: 2793

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53278

Other (OTH) AF: 0.00 AC: 0 AN: 1517

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.17
DANN	Benign	0.27
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.7	N
PhyloP100		1.0
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.042
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.038
MutPred		0.17		Gain of ubiquitination at R473 (P = 0.0054)
MVP		0.15
MPC		0.57
ClinPred		0.023	T
GERP RS		2.1
Varity_R		0.057
gMVP		0.42
Mutation Taster		=94/6	polymorphism

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: rs773189052; hg19: chrX-15339665; COSMIC: COSV109429011; COSMIC: COSV109429011;