17-36537207-A-G

Variant summary

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

The NM_001346754.2(PIGW):c.106A>G(p.Arg36Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000445 in 1,614,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: PIGW NM_001346754.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:1
• Conservation: PhyloP100: 2.98

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=0.19044587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGW	NM_001346754.2	c.106A>G	p.Arg36Gly	missense_variant	2/2	ENST00000614443.2
PIGW	NM_001346755.2	c.106A>G	p.Arg36Gly	missense_variant	2/2
PIGW	NM_178517.5	c.106A>G	p.Arg36Gly	missense_variant	2/2
MYO19	XM_047436823.1	c.-295-3103T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGW	ENST00000614443.2	c.106A>G	p.Arg36Gly	missense_variant	2/2	1	NM_001346754.2	P1

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000207 AC: 52 AN: 251484 Hom.: 0 AF XY: 0.000213 AC XY: 29 AN XY: 135916

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000458 AC: 670 AN: 1461850 Hom.: 0 Cov.: 32 AF XY: 0.000447 AC XY: 325 AN XY: 727228

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000573

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74498

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000543 Hom.: 0

Bravo AF: 0.000302

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000654

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperphosphatasia with intellectual disability syndrome 5 Pathogenic:1 Uncertain:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 09, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 26, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (62 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygote). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0803 - Low previous evidence of pathogenicity in unrelated individuals. This variant has been reported as homozygous and likely pathogenic in a family with 2 foetuses with Fryns or Fryns-like syndrome (PMID:30679815). It has also been reported as a VUS in ClinVar. (P) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 13, 2022	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 36 of the PIGW protein (p.Arg36Gly). This variant is present in population databases (rs142067039, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of PIGW-related conditions (PMID: 30679815). ClinVar contains an entry for this variant (Variation ID: 452328). 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 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. -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	PIGW: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32198969, 30679815) -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2022

The c.106A>G (p.R36G) alteration is located in exon 2 (coding exon 1) of the PIGW gene. This alteration results from a A to G substitution at nucleotide position 106, causing the arginine (R) at amino acid position 36 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T;.;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	.;D;D
Vest4		0.90, 0.89
MVP		0.42
ClinPred		0.25	T
GERP RS		4.7
Varity_R		0.69
gMVP		0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs142067039; hg19: chr17-34893056;