Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_176787.5(PIGN):c.1004C>G(p.Pro335Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P335L) has been classified 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 Uncertain_significance. Variant got 3 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, 0.776
Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);.;Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);