9-35088825-G-C

Variant names:

• chr9-35088825-G-C
• rs79276933
• NM_032634.4:c.*267C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032634.4(PIGO):​c.*267C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 370,864 control chromosomes in the GnomAD database, including 263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (220 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (43 hom.)
• Consequence: PIGO NM_032634.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.15
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-35088825-G-C is Benign according to our data. Variant chr9-35088825-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 366749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGO	NM_032634.4	c.*267C>G		3_prime_UTR_variant	Exon 11 of 11	ENST00000378617.4	NP_116023.2
PIGO	NM_001201484.2	c.*267C>G		3_prime_UTR_variant	Exon 13 of 13		NP_001188413.1
PIGO	NM_152850.4	c.*267C>G		3_prime_UTR_variant	Exon 12 of 12		NP_690577.2
PIGO	XM_005251619.4	c.*267C>G		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.*267C>G		3_prime_UTR_variant	Exon 11 of 11	1	NM_032634.4	ENSP00000367880.3

Frequencies

GnomAD3 genomes AF: 0.0287 AC: 4362 AN: 152142 Hom.: 221 Cov.: 32

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0158

GnomAD4 exome AF: 0.00384 AC: 840 AN: 218604 Hom.: 43 Cov.: 4 AF XY: 0.00326 AC XY: 376 AN XY: 115302

African (AFR) AF: 0.0972 AC: 685 AN: 7048

American (AMR) AF: 0.00532 AC: 49 AN: 9208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6564

East Asian (EAS) AF: 0.00 AC: 0 AN: 12736

South Asian (SAS) AF: 0.000302 AC: 8 AN: 26452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10414

Middle Eastern (MID) AF: 0.00321 AC: 3 AN: 936

European-Non Finnish (NFE) AF: 0.000105 AC: 14 AN: 132866

Other (OTH) AF: 0.00654 AC: 81 AN: 12380

GnomAD4 genome AF: 0.0287 AC: 4368 AN: 152260 Hom.: 220 Cov.: 32 AF XY: 0.0272 AC XY: 2026 AN XY: 74454

African (AFR) AF: 0.100 AC: 4156 AN: 41536

American (AMR) AF: 0.0105 AC: 161 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68014

Other (OTH) AF: 0.0156 AC: 33 AN: 2112

Alfa AF: 0.0211 Hom.: 18

Bravo AF: 0.0325

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hyperphosphatasia with intellectual disability syndrome 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.9
DANN	Benign	0.48
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs79276933; hg19: chr9-35088822;