Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_176787.5(PIGN):c.310G>C(p.Gly104Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.
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 6 ACMG points.
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, 0.984
Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);.;Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);Loss of catalytic residue at A103 (P = 0.0307);.;Loss of catalytic residue at A103 (P = 0.0307);