rs748093757
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_032634.4(PIGO):c.2197C>T(p.Arg733Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000732 in 1,612,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R733Q) has been classified as Benign.
Frequency
Consequence
NM_032634.4 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 |
---|---|---|---|---|---|---|---|
PIGO | NM_032634.4 | c.2197C>T | p.Arg733Trp | missense_variant | 7/11 | ENST00000378617.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIGO | ENST00000378617.4 | c.2197C>T | p.Arg733Trp | missense_variant | 7/11 | 1 | NM_032634.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152156Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000142 AC: 35AN: 245748Hom.: 1 AF XY: 0.000157 AC XY: 21AN XY: 134040
GnomAD4 exome AF: 0.0000685 AC: 100AN: 1460246Hom.: 0 Cov.: 31 AF XY: 0.0000702 AC XY: 51AN XY: 726486
GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152156Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74330
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 14, 2017 | A variant of uncertain significance has been identified in the PIGO gene. The R733W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R733W variant is observed in 13/6572 (0.2%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R733W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Hyperphosphatasia with intellectual disability syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 733 of the PIGO protein (p.Arg733Trp). This variant is present in population databases (rs748093757, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with PIGO-related conditions. ClinVar contains an entry for this variant (Variation ID: 432734). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at