rs115209243
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_153747.2(PIGC):c.61C>T(p.Arg21Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000725 in 1,613,960 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 0.00030 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000049 ( 0 hom. )
Consequence
PIGC
NM_153747.2 stop_gained
NM_153747.2 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.16
Genes affected
PIGC (HGNC:8960): (phosphatidylinositol glycan anchor biosynthesis class C) This gene encodes an endoplasmic reticulum associated protein that is involved in glycosylphosphatidylinositol (GPI) lipid anchor biosynthesis. The GPI lipid anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. The encoded protein is one subunit of the GPI N-acetylglucosaminyl (GlcNAc) transferase that transfers GlcNAc to phosphatidylinositol (PI) on the cytoplasmic side of the endoplasmic reticulum. Two alternatively spliced transcripts that encode the same protein have been found for this gene. A pseudogene on chromosome 11 has also been characterized. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-172442562-G-A is Pathogenic according to our data. Variant chr1-172442562-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 471153.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2, Pathogenic=1}. Variant chr1-172442562-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIGC | NM_153747.2 | c.61C>T | p.Arg21Ter | stop_gained | 2/2 | ENST00000344529.5 | |
C1orf105 | NM_139240.4 | c.22-2511G>A | intron_variant | ENST00000367727.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIGC | ENST00000344529.5 | c.61C>T | p.Arg21Ter | stop_gained | 2/2 | 1 | NM_153747.2 | P1 | |
C1orf105 | ENST00000367727.9 | c.22-2511G>A | intron_variant | 1 | NM_139240.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000302 AC: 46AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251434Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135898
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GnomAD4 exome AF: 0.0000486 AC: 71AN: 1461658Hom.: 0 Cov.: 34 AF XY: 0.0000413 AC XY: 30AN XY: 727148
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GnomAD4 genome ? AF: 0.000302 AC: 46AN: 152302Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15AN XY: 74472
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Glycosylphosphatidylinositol biosynthesis defect 16 Pathogenic:4
Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Oct 15, 2018 | This variant is interpreted as Likely Pathogenic, for Glycosylphosphatidylinositol biosynthesis defect 16, autosomal recessive. The following ACMG Tag(s) were applied: PVS1-Moderate => PVS1 downgraded in strength to Moderate. PS3-Moderate => PS3 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/27694521). PM2 => Recessive disease and allele present at low frequency in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 21, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Apr 10, 2022 | The c.61C>T;p.(Arg21)* variant creates a premature translational stop signal in the PIGC gene. It is expected to result in an absent or disrupted protein product -PVS1_moderate. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 27694521) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 471153; PMID: 27694521) - PS4. The variant is present at low allele frequencies population databases (rs115209243 – gnomAD 0.0007425%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br) - PM2_supporting. The p.(Arg21*) was detected in trans with a pathogenic variant (PMID: 27694521) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 27694521) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic - |
Likely pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jul 09, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 11, 2017 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D;D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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