rs199573774
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_176787.5(PIGN):āc.2679C>Gā(p.Ser893Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000955 in 1,612,328 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00015 ( 0 hom., cov: 32)
Exomes š: 0.000090 ( 0 hom. )
Consequence
PIGN
NM_176787.5 missense
NM_176787.5 missense
Scores
3
7
4
Clinical Significance
Conservation
PhyloP100: 1.96
Genes affected
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 18-62045973-G-C is Pathogenic according to our data. Variant chr18-62045973-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449082.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIGN | NM_176787.5 | c.2679C>G | p.Ser893Arg | missense_variant | 31/31 | ENST00000640252.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIGN | ENST00000640252.2 | c.2679C>G | p.Ser893Arg | missense_variant | 31/31 | 1 | NM_176787.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000151 AC: 23AN: 152208Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000134 AC: 33AN: 246180Hom.: 0 AF XY: 0.000157 AC XY: 21AN XY: 133356
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GnomAD4 exome AF: 0.0000897 AC: 131AN: 1460002Hom.: 0 Cov.: 30 AF XY: 0.0000937 AC XY: 68AN XY: 726052
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GnomAD4 genome ? AF: 0.000151 AC: 23AN: 152326Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74484
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Multiple congenital anomalies-hypotonia-seizures syndrome 1 Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 893 of the PIGN protein (p.Ser893Arg). This variant is present in population databases (rs199573774, gnomAD 0.04%). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy and/or PIGN-related disease (PMID: 35179230, 36322149; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 449082). 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 expected to disrupt PIGN protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Apr 23, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | This variant was identified as compound heterozygous. - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 16, 2022 | Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 22, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27119594, 26633542, 34426522) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;.;T;T;T;.;.;.;.;.;T;.;.;T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;.;M;M;M;.;.;.;.;.;M;.;.;M;.;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Polyphen
D;.;D;D;D;.;.;.;.;.;D;.;.;D;.;D
Vest4
0.89, 0.90
MutPred
Loss of glycosylation at S891 (P = 0.1612);.;Loss of glycosylation at S891 (P = 0.1612);Loss of glycosylation at S891 (P = 0.1612);Loss of glycosylation at S891 (P = 0.1612);.;.;.;.;.;Loss of glycosylation at S891 (P = 0.1612);.;.;Loss of glycosylation at S891 (P = 0.1612);.;Loss of glycosylation at S891 (P = 0.1612);
MVP
0.70
MPC
0.20
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at