rs368953604
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_032634.4(PIGO):c.3069+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,611,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000037 ( 0 hom. )
Consequence
PIGO
NM_032634.4 splice_region, intron
NM_032634.4 splice_region, intron
Scores
2
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 2.42
Genes affected
PIGO (HGNC:23215): (phosphatidylinositol glycan anchor biosynthesis class O) This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid which contains three mannose molecules in its core backbone. The GPI-anchor is found on many blood cells and serves to anchor proteins to the cell surface. This protein is involved in the transfer of ethanolaminephosphate (EtNP) to the third mannose in GPI. At least three alternatively spliced transcripts encoding two distinct isoforms have been found for this gene. [provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-35090061-C-T is Pathogenic according to our data. Variant chr9-35090061-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35090061-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PIGO | NM_032634.4 | c.3069+5G>A | splice_region_variant, intron_variant | Intron 9 of 10 | ENST00000378617.4 | NP_116023.2 | ||
| PIGO | NM_001201484.2 | c.1818+5G>A | splice_region_variant, intron_variant | Intron 11 of 12 | NP_001188413.1 | |||
| PIGO | NM_152850.4 | c.1818+5G>A | splice_region_variant, intron_variant | Intron 10 of 11 | NP_690577.2 | |||
| PIGO | XM_005251619.4 | c.3069+5G>A | splice_region_variant, intron_variant | Intron 9 of 10 | XP_005251676.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000394 AC: 6AN: 152232Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250908Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135592
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GnomAD4 exome AF: 0.0000370 AC: 54AN: 1459550Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26AN XY: 725616
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GnomAD4 genome 0.0000394 AC: 6AN: 152232Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74362
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hyperphosphatasia with intellectual disability syndrome 2 Pathogenic:4
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 13, 2012 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 30, 2019 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2025 | This sequence change falls in intron 9 of the PIGO gene. It does not directly change the encoded amino acid sequence of the PIGO protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs368953604, gnomAD 0.009%). This variant has been observed in individual(s) with clinical features of PIGN-congenital disorder of glycosylation (PMID: 22683086). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 35601). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 9, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 22683086). 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 21, 2024 | Variant summary: PIGO c.3069+5G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. One predict the variant creates a cryptic 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing by exon skipping (Krawitz_2012). The variant allele was found at a frequency of 2.8e-05 in 250908 control chromosomes. c.3069+5G>A has been reported in the literature in at-least one individual affected with Hyperphosphatasia With Intellectual Disability Syndrome (Krawitz_2012). These data do not allow any conclusion about variant significance. The following publications have been ascertained in the context of this evaluation (PMID: 31589614, 22683086, 34493867). ClinVar contains an entry for this variant (Variation ID: 35601). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 16, 2022 | Non-canonical splice site variant demonstrated to result in loss of function (Krawitz et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22683086, 28900819, 26219719, 31589614, 31127708, 31698102) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at