NM_032634.4:c.2872C>A

Variant names:

• chr9-35090263-G-T
• rs991755076
• NM_032634.4:c.2872C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032634.4(PIGO):​c.2872C>A​(p.Leu958Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,520 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L958L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PIGO NM_032634.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.52
• 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, Labcorp Genetics (formerly Invitae), Illumina
• hyperphosphatasia-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032634.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGO	NM_032634.4	MANE Select	c.2872C>A	p.Leu958Met	missense	Exon 9 of 11	NP_116023.2
	PIGO	NM_001201484.2		c.1621C>A	p.Leu541Met	missense	Exon 11 of 13	NP_001188413.1	Q8TEQ8-2
	PIGO	NM_152850.4		c.1621C>A	p.Leu541Met	missense	Exon 10 of 12	NP_690577.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGO	ENST00000378617.4	TSL:1 MANE Select	c.2872C>A	p.Leu958Met	missense	Exon 9 of 11	ENSP00000367880.3	Q8TEQ8-1
	PIGO	ENST00000298004.9	TSL:1	c.1621C>A	p.Leu541Met	missense	Exon 11 of 13	ENSP00000298004.5	Q8TEQ8-2
	PIGO	ENST00000907113.1		c.2872C>A	p.Leu958Met	missense	Exon 9 of 11	ENSP00000577172.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461520 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727016

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111822

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hyperphosphatasia with intellectual disability syndrome 2 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.047	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.44		Loss of catalytic residue at L958 (P = 4e-04)
MVP		0.71
MPC		0.59
ClinPred		0.78	D
GERP RS		2.2
Varity_R		0.16
gMVP		0.45
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs991755076; hg19: chr9-35090260;