rs1555945533

chrX-15331819-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. 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

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 Uncertain_significance. Variant got 4 ACMG points.

• 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 id is 390052.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGA	NM_002641.4	c.112G>A	p.Val38Ile	missense_variant	2/6	ENST00000333590.6
PIGA	NM_020473.3	c.13+3682G>A		intron_variant
PIGA	NR_033835.1	n.228G>A		non_coding_transcript_exon_variant	2/6
PIGA	NR_033836.1	n.173+55G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGA	ENST00000333590.6	c.112G>A	p.Val38Ile	missense_variant	2/6	1	NM_002641.4	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000369

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

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

Oct 03, 2017

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PIGA-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 38 of the PIGA protein (p.Val38Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

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;T;.;.
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.0	M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.85	N;.;.;.
REVEL	Uncertain	0.33
Sift	Benign	0.090	T;.;.;.
Sift4G	Benign	0.13	T;T;T;.
Polyphen		1.0	D;D;D;.
Vest4		0.48
MutPred		0.61		Loss of catalytic residue at V38 (P = 0.0429);Loss of catalytic residue at V38 (P = 0.0429);Loss of catalytic residue at V38 (P = 0.0429);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

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: rs1555945533; hg19: chrX-15349941;