Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_176787.5(PIGN):c.806G>T(p.Gly269Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000793 in 1,261,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
PIGN (HGNC:8967): (phosphatidylinositol glycan anchor biosynthesis class N) This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This protein is expressed in the endoplasmic reticulum and transfers phosphoethanolamine (EtNP) to the first mannose of the GPI anchor. Two alternatively spliced variants, which encode an identical isoform, have been reported. [provided by RefSeq, Jul 2008]
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_176787.5
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.96
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Aug 31, 2021
This sequence change replaces glycine with valine at codon 269 of the PIGN protein (p.Gly269Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PIGN-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);.;.;Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);Loss of disorder (P = 0.0318);