X-15321574-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002641.4(PIGA):c.1387G>A(p.Ala463Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000832 in 1,201,397 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: PIGA NM_002641.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.207

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09469706).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGA	NM_002641.4	c.1387G>A	p.Ala463Thr	missense_variant	6/6	ENST00000333590.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGA	ENST00000333590.6	c.1387G>A	p.Ala463Thr	missense_variant	6/6	1	NM_002641.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000356 AC: 4 AN: 112371 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34521

Gnomad AFR AF: 0.000130

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000163 AC: 3 AN: 183487 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67923

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000551 AC: 6 AN: 1089026 Hom.: 0 Cov.: 28 AF XY: 0.00000564 AC XY: 2 AN XY: 354568

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000437

GnomAD4 genome AF: 0.0000356 AC: 4 AN: 112371 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34521

Gnomad4 AFR AF: 0.000130

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000567

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 05, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PIGA protein function. ClinVar contains an entry for this variant (Variation ID: 1014456). This variant has not been reported in the literature in individuals affected with PIGA-related conditions. This variant is present in population databases (rs774546648, gnomAD 0.02%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 463 of the PIGA protein (p.Ala463Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	3.6
Dann	Benign	0.80
DEOGEN2	Benign	0.13	T;T;T;.;.;.
FATHMM_MKL	Benign	0.19	N
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.095	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;.;.;.;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.29	N;.;.;.;.;.
REVEL	Benign	0.022
Sift	Benign	0.17	T;.;.;.;.;.
Sift4G	Benign	0.50	T;T;.;T;T;.
Polyphen		0.0	B;B;.;.;B;.
Vest4		0.043
MutPred		0.26		Loss of catalytic residue at A463 (P = 0.0099);Loss of catalytic residue at A463 (P = 0.0099);.;.;.;.;
MVP		0.53
MPC		0.54
ClinPred		0.058	T
GERP RS		1.8
Varity_R		0.039
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs774546648; hg19: chrX-15339696;