chr17-36537116-G-T

Position:

• chr17-36537116-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001346754.2(PIGW):​c.15G>T​(p.Gln5His) 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. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIGW NM_001346754.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.991

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.097584754).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGW	NM_001346754.2	c.15G>T	p.Gln5His	missense_variant	2/2	ENST00000614443.2	NP_001333683.1
PIGW	NM_001346755.2	c.15G>T	p.Gln5His	missense_variant	2/2		NP_001333684.1
PIGW	NM_178517.5	c.15G>T	p.Gln5His	missense_variant	2/2		NP_848612.2
MYO19	XM_047436823.1	c.-295-3012C>A		intron_variant			XP_047292779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGW	ENST00000614443.2	c.15G>T	p.Gln5His	missense_variant	2/2	1	NM_001346754.2	ENSP00000482202	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperphosphatasia with intellectual disability syndrome 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 5 of the PIGW protein (p.Gln5His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PIGW-related conditions. ClinVar contains an entry for this variant (Variation ID: 2012882). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PIGW protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.0088	.;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.032
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.60	T;.;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.098	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	.;M;M
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.45	T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.016	.;B;B
Vest4		0.061, 0.060
MutPred		0.21		Loss of methylation at K7 (P = 0.1079);Loss of methylation at K7 (P = 0.1079);Loss of methylation at K7 (P = 0.1079);
MVP		0.33
ClinPred		0.13	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.057
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-34892965;