rs1060499763
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_176787.5(PIGN):c.996T>G(p.Ile332Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000193 in 1,555,486 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I332V) has been classified as Uncertain significance.
Frequency
Consequence
NM_176787.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIGN | NM_176787.5 | c.996T>G | p.Ile332Met | missense_variant | 12/31 | ENST00000640252.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIGN | ENST00000640252.2 | c.996T>G | p.Ile332Met | missense_variant | 12/31 | 1 | NM_176787.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000143 AC: 2AN: 1403320Hom.: 0 Cov.: 22 AF XY: 0.00000143 AC XY: 1AN XY: 697096
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Multiple congenital anomalies-hypotonia-seizures syndrome 1 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 22, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 402190). This missense change has been observed in individual(s) with clinical features of PIGN congenital disorder of glycosylation (PMID: 26539891, 33619735, 35179230). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 332 of the PIGN protein (p.Ile332Met). - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Dec 06, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
Abnormal brain morphology Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | - | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 15, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26539891, 33619735, 36322149, 35179230) - |
PIGN-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 07, 2022 | The PIGN c.996T>G variant is predicted to result in the amino acid substitution p.Ile332Met. This variant has been reported in the homozygous and compound heterozygous state with a premature termination variant in two individuals with PIGN-related phenotypes (Karaca et al 2015. PubMed ID: 26539891, Sup Table 1A; Brunet T et al 2021. PubMed ID: 33619735, Supp Table). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (1 allele, http://gnomad.broadinstitute.org/variant/18-59807680-A-C), indicating it is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at