20-45420368-C-T
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_015937.6(PIGT):c.806C>T(p.Thr269Met) variant causes a missense change. The variant allele was found at a frequency of 0.00107 in 1,613,680 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00070 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 1 hom. )
Consequence
PIGT
NM_015937.6 missense
NM_015937.6 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: 5.47
Genes affected
PIGT (HGNC:14938): (phosphatidylinositol glycan anchor biosynthesis class T) 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 an essential component of the multisubunit enzyme, GPI transamidase. GPI transamidase mediates GPI anchoring in the endoplasmic reticulum, by catalyzing the transfer of fully assembled GPI units to proteins. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.039145052).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000703 (107/152212) while in subpopulation NFE AF= 0.00121 (82/68028). AF 95% confidence interval is 0.000995. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIGT | NM_015937.6 | c.806C>T | p.Thr269Met | missense_variant | 7/12 | ENST00000279036.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIGT | ENST00000279036.12 | c.806C>T | p.Thr269Met | missense_variant | 7/12 | 1 | NM_015937.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000704 AC: 107AN: 152094Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000527 AC: 132AN: 250380Hom.: 0 AF XY: 0.000465 AC XY: 63AN XY: 135344
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GnomAD4 exome AF: 0.00111 AC: 1618AN: 1461468Hom.: 1 Cov.: 31 AF XY: 0.00106 AC XY: 773AN XY: 727004
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GnomAD4 genome AF: 0.000703 AC: 107AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39AN XY: 74408
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 14, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 04, 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 - |
Multiple congenital anomalies-hypotonia-seizures syndrome 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 269 of the PIGT protein (p.Thr269Met). This variant is present in population databases (rs149740779, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PIGT-related conditions. ClinVar contains an entry for this variant (Variation ID: 377166). 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 PIGT protein function with a negative 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;L;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;.;.;.;.;.;.;.;.;.;.;.
REVEL
Benign
Sift
Benign
T;T;T;T;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Benign
T;T;T;T;.;.;.;.;.;.;.;.;.;.;.
Polyphen
D;P;.;.;.;.;.;.;.;.;.;.;.;D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
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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