chr17-36537116-G-C

Position:

• chr17-36537116-G-C

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>C​(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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• 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=0.09103614).

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000139 AC: 2 AN: 1438798 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 714314

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000337

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.00231 AC: 8 AN: 3478

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

Jul 21, 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). 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. 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. ClinVar contains an entry for this variant (Variation ID: 2042973). This variant has not been reported in the literature in individuals affected with PIGW-related conditions. This variant is not present in population databases (gnomAD no frequency). -

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	18
DANN	Benign	0.93
DEOGEN2	Benign	0.0088	.;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.032
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.60	T;.;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.091	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

LitVar

Other links and lift over

dbSNP: rs1053869803; hg19: chr17-34892965;