rs774753616
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_015937.6(PIGT):c.550G>A(p.Glu184Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
PIGT
NM_015937.6 missense
NM_015937.6 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 9.35
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_pathogenic. Variant got 7 ACMG points.
PM1
?
In a helix (size 8) in uniprot entity PIGT_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_015937.6
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.895
PP5
?
Variant 20-45419351-G-A is Pathogenic according to our data. Variant chr20-45419351-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547166.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr20-45419351-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIGT | NM_015937.6 | c.550G>A | p.Glu184Lys | missense_variant | 4/12 | ENST00000279036.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIGT | ENST00000279036.12 | c.550G>A | p.Glu184Lys | missense_variant | 4/12 | 1 | NM_015937.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251190Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135730
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461768Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727178
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74364
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Multiple congenital anomalies-hypotonia-seizures syndrome 3 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 20, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 184 of the PIGT protein (p.Glu184Lys). This variant is present in population databases (rs774753616, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of PIGT-related conditions (PMID: 29868109, 30049826, 30976099, 31130284). This variant is also known as NM_001184730.2:c.244G>A:p.Glu82Lys. ClinVar contains an entry for this variant (Variation ID: 547166). 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 PIGT 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Translational Omics - GOSgene, University College London | Mar 16, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;.;.;.;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;.;H;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;.;.;.;.;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;.;.;.;.;.;.
Sift4G
Uncertain
D;D;D;D;.;.;.;.;.;.
Polyphen
D;D;.;.;.;.;.;.;.;.
Vest4
MVP
MPC
ClinPred
D
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