9-35090266-G-A

Position:

• chr9-35090266-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_032634.4(PIGO):​c.2869C>T​(p.Leu957Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,490 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: PIGO NM_032634.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.27

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]

PIGO (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.779
• PP5: Variant 9-35090266-G-A is Pathogenic according to our data. Variant chr9-35090266-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35090266-G-A is described in Lovd as [Pathogenic]. Variant chr9-35090266-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGO	NM_032634.4	c.2869C>T	p.Leu957Phe	missense_variant	9/11	ENST00000378617.4	NP_116023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGO	ENST00000378617.4	c.2869C>T	p.Leu957Phe	missense_variant	9/11	1	NM_032634.4	ENSP00000367880.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461490 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726996

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

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: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000326 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperphosphatasia with intellectual disability syndrome 2 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 11, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 13, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 14, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PIGO function (PMID: 22683086). 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 not expected to disrupt PIGO protein function. ClinVar contains an entry for this variant (Variation ID: 35599). This missense change has been observed in individual(s) with PIGO-related conditions (PMID: 22683086). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 957 of the PIGO protein (p.Leu957Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	0.047	D
MutationAssessor	Uncertain	2.2	.;.;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.79	N;N;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0060	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.73
MVP		0.94
MPC		0.68
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.48
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs142164373; hg19: chr9-35090263;