chr4-523849-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_001127178.3(PIGG):c.2005C>T(p.Arg669Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000094 in 1,595,968 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R669H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001127178.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIGG | NM_001127178.3 | c.2005C>T | p.Arg669Cys | missense_variant | 9/13 | ENST00000453061.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIGG | ENST00000453061.7 | c.2005C>T | p.Arg669Cys | missense_variant | 9/13 | 1 | NM_001127178.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000985 AC: 15AN: 152224Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000667 AC: 14AN: 209920Hom.: 0 AF XY: 0.0000525 AC XY: 6AN XY: 114352
GnomAD4 exome AF: 0.0000935 AC: 135AN: 1443628Hom.: 1 Cov.: 32 AF XY: 0.0000990 AC XY: 71AN XY: 716814
GnomAD4 genome ? AF: 0.0000985 AC: 15AN: 152340Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5AN XY: 74478
ClinVar
Submissions by phenotype
Intellectual disability, autosomal recessive 53 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 20, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 669 of the PIGG protein (p.Arg669Cys). This variant is present in population databases (rs372392424, gnomAD 0.02%). This missense change has been observed in individual(s) with intellectual disability, seizures, and hypotonia (PMID: 26996948). ClinVar contains an entry for this variant (Variation ID: 225638). 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 PIGG protein function with a positive predictive value of 80%. 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. - |
Hyperphosphatasia with intellectual disability syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn | - | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 29, 2023 | Published functional studies demonstrate a damaging effect: impairs the conversion of GPI precursor H7 to H8 (Makrythanasis et al., 2016); 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: Ishida2020[Functional Study], 27870114, 26996948) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at