9-35094245-T-G

Variant names:

• chr9-35094245-T-G
• rs138028827
• NM_032634.4:c.626A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032634.4(PIGO):​c.626A>C​(p.Asn209Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N209S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIGO NM_032634.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.49
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28592706).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGO	NM_032634.4	MANE Select	c.626A>C	p.Asn209Thr	missense	Exon 3 of 11	NP_116023.2
	PIGO	NM_001201484.2		c.626A>C	p.Asn209Thr	missense	Exon 4 of 13	NP_001188413.1
	PIGO	NM_152850.4		c.626A>C	p.Asn209Thr	missense	Exon 3 of 12	NP_690577.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGO	ENST00000378617.4	TSL:1 MANE Select	c.626A>C	p.Asn209Thr	missense	Exon 3 of 11	ENSP00000367880.3
	PIGO	ENST00000298004.9	TSL:1	c.626A>C	p.Asn209Thr	missense	Exon 4 of 13	ENSP00000298004.5
	PIGO	ENST00000700261.1		c.626A>C	p.Asn209Thr	missense	Exon 3 of 12	ENSP00000514897.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.070
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.5
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.16
Sift	Benign	0.098	T
Sift4G	Benign	0.092	T
Polyphen		0.29	B
Vest4		0.39
MutPred		0.26		Gain of loop (P = 0.0851)
MVP		0.77
MPC		0.38
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.71
Mutation Taster		=64/36	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: rs138028827; hg19: chr9-35094242;