rs201146360
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The ENST00000453061.7(PIGG):āc.1298A>Gā(p.Tyr433Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000799 in 1,614,014 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 Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000072 ( 0 hom., cov: 33)
Exomes š: 0.000081 ( 0 hom. )
Consequence
PIGG
ENST00000453061.7 missense
ENST00000453061.7 missense
Scores
4
11
4
Clinical Significance
Conservation
PhyloP100: 7.04
Genes affected
PIGG (HGNC:25985): (phosphatidylinositol glycan anchor biosynthesis class G (EMM blood group)) This gene encodes an enzyme involved in glycosylphosphatidylinositol-anchor biosynthesis. The encoded protein, which is localized to the endoplasmic reticulum, is involved in transferring ethanoloamine phosphate to mannose 2 of glycosylphosphatidylinositol species H7 to form species H8. Allelic variants of this gene have been associated with intellectual disability, hypotonia, and early-onset seizures. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.953
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PIGG | NM_001127178.3 | c.1298A>G | p.Tyr433Cys | missense_variant | 7/13 | ENST00000453061.7 | NP_001120650.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PIGG | ENST00000453061.7 | c.1298A>G | p.Tyr433Cys | missense_variant | 7/13 | 1 | NM_001127178.3 | ENSP00000415203 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152194Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251444Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135892
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GnomAD4 exome AF: 0.0000807 AC: 118AN: 1461702Hom.: 0 Cov.: 31 AF XY: 0.0000633 AC XY: 46AN XY: 727124
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GnomAD4 genome AF: 0.0000722 AC: 11AN: 152312Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2AN XY: 74492
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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 specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 30, 2024 | Variant summary: PIGG c.1298A>G (p.Tyr433Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251444 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1298A>G in individuals affected with Intellectual Disability, Autosomal Recessive 53 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 542886). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 29, 2022 | The c.1298A>G (p.Y433C) alteration is located in exon 7 (coding exon 7) of the PIGG gene. This alteration results from a A to G substitution at nucleotide position 1298, causing the tyrosine (Y) at amino acid position 433 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Intellectual disability, autosomal recessive 53 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 15, 2022 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 433 of the PIGG protein (p.Tyr433Cys). This variant is present in population databases (rs201146360, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with PIGG-related conditions. ClinVar contains an entry for this variant (Variation ID: 542886). 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: "Tolerated"; PolyPhen-2: "Probably 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;T
Polyphen
D;D;.;D;D
Vest4
MutPred
Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;.;.;
MVP
MPC
0.78
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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