chr17-36537226-T-G

Variant names:

• chr17-36537226-T-G
• NM_001346754.2:c.125T>G

Variant summary

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

The NM_001346754.2(PIGW):​c.125T>G​(p.Phe42Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F42F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIGW NM_001346754.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.42
• Publications: 0 publications found

Genes affected

PIGW (HGNC:23213): (phosphatidylinositol glycan anchor biosynthesis class W) The protein encoded by this gene is an inositol acyltransferase that acylates the inositol ring of phosphatidylinositol. This occurs in the endoplasmic reticulum and is a step in the biosynthesis of glycosylphosphatidylinositol (GPI), which anchors many cell surface proteins to the membrane. Defects in this gene are a cause of the age-dependent epileptic encephalopathy West syndrome as well as a syndrome exhibiting hyperphosphatasia and cognitive disability (HPMRS5). [provided by RefSeq, Jul 2017]

MYO19 (HGNC:26234): (myosin XIX) Enables actin binding activity. Involved in regulation of cytokinesis and regulation of mitochondrial fission. Acts upstream of or within mitochondrion migration along actin filament. Located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.27989805).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346754.2. 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
	PIGW	NM_001346754.2	MANE Select	c.125T>G	p.Phe42Cys	missense	Exon 2 of 2	NP_001333683.1	Q7Z7B1
	PIGW	NM_001346755.2		c.125T>G	p.Phe42Cys	missense	Exon 2 of 2	NP_001333684.1	Q7Z7B1
	PIGW	NM_178517.5		c.125T>G	p.Phe42Cys	missense	Exon 2 of 2	NP_848612.2	Q7Z7B1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGW	ENST00000614443.2	TSL:1 MANE Select	c.125T>G	p.Phe42Cys	missense	Exon 2 of 2	ENSP00000482202.1	Q7Z7B1
	PIGW	ENST00000619326.1	TSL:1	c.125T>G	p.Phe42Cys	missense	Exon 2 of 2	ENSP00000480475.1	A0A087WWS9
	PIGW	ENST00000620233.1	TSL:2	c.125T>G	p.Phe42Cys	missense	Exon 2 of 2	ENSP00000480021.1	Q7Z7B1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.0088	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.029	T
Eigen	Benign	0.012
Eigen_PC	Benign	0.068
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.4
PrimateAI	Benign	0.28	T
Sift4G	Uncertain	0.011	D
Polyphen		0.84	P
Vest4		0.20
MutPred		0.58		Gain of catalytic residue at F42 (P = 0.1477)
MVP		0.51
ClinPred		0.55	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.26

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

hg19: chr17-34893075;