rs149171782

Positions:

• chr9-35091619-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_032634.4(PIGO):​c.2268G>A​(p.Ala756=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,613,526 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (25 hom.)
• Consequence: PIGO NM_032634.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.29

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 9-35091619-C-T is Benign according to our data. Variant chr9-35091619-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198602.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=1.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00299 (456/152270) while in subpopulation NFE AF= 0.00521 (354/68008). AF 95% confidence interval is 0.00476. There are 1 homozygotes in gnomad4. There are 177 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGO	NM_032634.4	c.2268G>A	p.Ala756=	synonymous_variant	7/11	ENST00000378617.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGO	ENST00000378617.4	c.2268G>A	p.Ala756=	synonymous_variant	7/11	1	NM_032634.4	P1

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 456 AN: 152152 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00520

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00234 AC: 582 AN: 248672 Hom.: 2 AF XY: 0.00236 AC XY: 319 AN XY: 135078

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00408

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.00477 AC: 6975 AN: 1461256 Hom.: 25 Cov.: 31 AF XY: 0.00460 AC XY: 3345 AN XY: 726980

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.000303

Gnomad4 NFE exome AF: 0.00588

Gnomad4 OTH exome AF: 0.00459

GnomAD4 genome AF: 0.00299 AC: 456 AN: 152270 Hom.: 1 Cov.: 33 AF XY: 0.00238 AC XY: 177 AN XY: 74456

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00521

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00349 Hom.: 2

Bravo AF: 0.00296

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00433

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PIGO: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 15, 2018	- -

Hyperphosphatasia with intellectual disability syndrome 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	5.4
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs149171782; hg19: chr9-35091616; COSMIC: COSV99956610; COSMIC: COSV99956610;