rs774508288

chr9-35092076-C-CG

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 18P and 1B. PVS1 PM2 PP5_Very_Strong BS1_Supporting

The NM_032634.4(PIGO):c.1810_1811insC(p.Arg604ProfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000302 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: PIGO NM_032634.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.794

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-35092076-C-CG is Pathogenic according to our data. Variant chr9-35092076-C-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 286126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000319 (466/1461870) while in subpopulation NFE AF= 0.000407 (453/1112002). AF 95% confidence interval is 0.000376. There are 0 homozygotes in gnomad4_exome. There are 238 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGO	NM_032634.4	c.1810_1811insC	p.Arg604ProfsTer40	frameshift_variant	7/11	ENST00000378617.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGO	ENST00000378617.4	c.1810_1811insC	p.Arg604ProfsTer40	frameshift_variant	7/11	1	NM_032634.4	P1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000151 AC: 38 AN: 251232 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000319 AC: 466 AN: 1461870 Hom.: 0 Cov.: 33 AF XY: 0.000327 AC XY: 238 AN XY: 727232

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: 0.0000187

Gnomad4 NFE exome AF: 0.000407

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74362

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000340 Hom.: 0

Bravo AF: 0.000208

EpiCase AF: 0.000436

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperphosphatasia with intellectual disability syndrome 2 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 11, 2023	Variant summary: PIGO c.1810dupC (p.Arg604ProfsX40) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00015 in 251232 control chromosomes (gnomAD). c.1810dupC has been reported in the literature in an individual affected with PIGO deficiency (example: Morren_2017). The following publication has been ascertained in the context of this evaluation (PMID: 28545593). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 27, 2022	This sequence change creates a premature translational stop signal (p.Arg604Profs*40) in the PIGO gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PIGO are known to be pathogenic (PMID: 22683086, 24417746). This variant is present in population databases (rs774508288, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with a PIGO-related disorder (PMID: 28545593). ClinVar contains an entry for this variant (Variation ID: 286126). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 22, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30609409, 22683086, 34313030, 24417746, 31980526, 31589614, 28545593, 31440721) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2022

The c.1810dupC (p.R604Pfs*40) alteration, located in exon 7 (coding exon 6) of the PIGO gene, consists of a duplication of C at position 1810, causing a translational frameshift with a predicted alternate stop codon after 40 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the dupC allele has an overall frequency of 0.02% (44/282630) total alleles studied. The highest observed frequency was 0.03% (42/129018) of European (non-Finnish) alleles. This alteration has been reported compound heterozygous in a patient with facial dysmorphism, psychomotor disability, epilepsy, palmoplantar keratoderma, hyperphosphatasemia, and platelet dysfunction without a clinical bleeding phenotype (Morren, 2017). Based on the available evidence, this alteration is classified as pathogenic. -

Hyperphosphatasia-intellectual disability syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 29, 2017

The p.Arg604ProfsX40 variant in PIGO has not been previously reported in indivi duals with hyperphosphatasia with intellectual disability syndrome, but has been reported in ClinVar (Variation ID#286126). It has been identified in 0.033% (42 /126,578) European chromosomes by the Genome Aggregation Database (http://gnomad .broadinstitute.org; dbSNP rs774508288). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a rece ssive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 604 and leads to a premature termination codon 40 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the PIGO gene has been associated with hyperphosphatasia with intellectual di sability syndrome. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg604ProfsX40 variant is likely pat hogenic for hyperphosphatasia with intellectual disability syndrome in an autoso mal recessive manner based on a predicted variant effect. ACMG/AMP Criteria appl ied: PVS1; PM2 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs774508288; hg19: chr9-35092073;