rs368953604

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

Scores

2
Splicing: ADA: 0.9999
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.42
Variant links:
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]

Genome browser will be placed here

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
PIGONM_032634.4 linkc.3069+5G>A splice_region_variant, intron_variant Intron 9 of 10 ENST00000378617.4 NP_116023.2 Q8TEQ8-1
PIGONM_001201484.2 linkc.1818+5G>A splice_region_variant, intron_variant Intron 11 of 12 NP_001188413.1 Q8TEQ8-2
PIGONM_152850.4 linkc.1818+5G>A splice_region_variant, intron_variant Intron 10 of 11 NP_690577.2 Q8TEQ8-2
PIGOXM_005251619.4 linkc.3069+5G>A splice_region_variant, intron_variant Intron 9 of 10 XP_005251676.1 Q8TEQ8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PIGOENST00000378617.4 linkc.3069+5G>A splice_region_variant, intron_variant Intron 9 of 10 1 NM_032634.4 ENSP00000367880.3 Q8TEQ8-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152232
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
250908
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135592
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000529
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000370
AC:
54
AN:
1459550
Hom.:
0
Cov.:
31
AF XY:
0.0000358
AC XY:
26
AN XY:
725616
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000459
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152232
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.00000961
Hom.:
0
Bravo
AF:
0.0000302
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

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
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJul 30, 2019- -
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 21, 2024Variant 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. -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 13, 2012- -
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 11, 2025This 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. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 16, 2022Non-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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.20
CADD
Benign
21
DANN
Benign
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.97
SpliceAI score (max)
0.76
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.76
Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs368953604; hg19: chr9-35090058; API