18-62113196-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_176787.5(PIGN):c.1372G>A(p.Ala458Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000067 in 1,612,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A458A) has been classified as Likely benign.
Frequency
Consequence
NM_176787.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIGN | NM_176787.5 | c.1372G>A | p.Ala458Thr | missense_variant | 16/31 | ENST00000640252.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIGN | ENST00000640252.2 | c.1372G>A | p.Ala458Thr | missense_variant | 16/31 | 1 | NM_176787.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152102Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000969 AC: 24AN: 247722Hom.: 0 AF XY: 0.000104 AC XY: 14AN XY: 134404
GnomAD4 exome AF: 0.0000609 AC: 89AN: 1460466Hom.: 0 Cov.: 31 AF XY: 0.0000661 AC XY: 48AN XY: 726498
GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74408
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 16, 2017 | The p.A458T variant (also known as c.1372G>A), located in coding exon 13 of the PIGN gene, results from a G to A substitution at nucleotide position 1372. The alanine at codon 458 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Multiple congenital anomalies-hypotonia-seizures syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 458 of the PIGN protein (p.Ala458Thr). This variant is present in population databases (rs370794466, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with PIGN-related conditions. ClinVar contains an entry for this variant (Variation ID: 472209). 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 not expected to disrupt PIGN protein function. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 17, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at