9-35088871-C-T

Variant names:

• chr9-35088871-C-T
• rs1056995769
• NM_032634.4:c.*221G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_032634.4(PIGO):​c.*221G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 573,816 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00068 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: PIGO NM_032634.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0890
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hyperphosphatasia with intellectual disability syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hyperphosphatasia-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000684 (104/152104) while in subpopulation AFR AF = 0.00244 (101/41418). AF 95% confidence interval is 0.00205. There are 1 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGO	NM_032634.4	c.*221G>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000378617.4	NP_116023.2
PIGO	NM_001201484.2	c.*221G>A		3_prime_UTR_variant	Exon 13 of 13		NP_001188413.1
PIGO	NM_152850.4	c.*221G>A		3_prime_UTR_variant	Exon 12 of 12		NP_690577.2
PIGO	XM_005251619.4	c.*221G>A		3_prime_UTR_variant	Exon 11 of 11		XP_005251676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGO	ENST00000378617.4	c.*221G>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_032634.4	ENSP00000367880.3

Frequencies

GnomAD3 genomes AF: 0.000684 AC: 104 AN: 152104 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000593 AC: 25 AN: 421712 Hom.: 0 Cov.: 6 AF XY: 0.0000362 AC XY: 8 AN XY: 220786

African (AFR) AF: 0.00168 AC: 20 AN: 11940

American (AMR) AF: 0.0000643 AC: 1 AN: 15554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10878

East Asian (EAS) AF: 0.00 AC: 0 AN: 23958

South Asian (SAS) AF: 0.00 AC: 0 AN: 38940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1622

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 274170

Other (OTH) AF: 0.000179 AC: 4 AN: 22390

GnomAD4 genome AF: 0.000684 AC: 104 AN: 152104 Hom.: 1 Cov.: 32 AF XY: 0.000686 AC XY: 51 AN XY: 74298

African (AFR) AF: 0.00244 AC: 101 AN: 41418

American (AMR) AF: 0.000197 AC: 3 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000744

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperphosphatasia with intellectual disability syndrome 2 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.9
DANN	Benign	0.43
PhyloP100		-0.089
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1056995769; hg19: chr9-35088868;