rs753385776

chr17-36537715-CTGTT-Cchr17-36537715-CTGTT-CTGTTTGTT

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_001346754.2(PIGW):c.617_620del(p.Val206GlyfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.000195 in 1,614,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

PIGW
NM_001346754.2 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:4

Conservation

PhyloP100: 4.65

Variant links:

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]

PIGW links:

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]

MYO19 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-36537715-CTGTT-C is Pathogenic according to our data. Variant chr17-36537715-CTGTT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377301.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=4, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PIGW	NM_001346754.2 linkuse as main transcript	c.617_620del	p.Val206GlyfsTer3	frameshift_variant	2/2	ENST00000614443.2
PIGW	NM_001346755.2 linkuse as main transcript	c.617_620del	p.Val206GlyfsTer3	frameshift_variant	2/2
PIGW	NM_178517.5 linkuse as main transcript	c.617_620del	p.Val206GlyfsTer3	frameshift_variant	2/2
MYO19	XM_047436823.1 linkuse as main transcript	c.-295-3615_-295-3612del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGW	ENST00000614443.2 linkuse as main transcript	c.617_620del	p.Val206GlyfsTer3	frameshift_variant	2/2	1	NM_001346754.2	P1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000255

AC:

AN:

251406

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000809

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000194

AC:

283

AN:

1461876

Hom.:

AF XY:

0.000194

AC XY:

141

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000529

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000167

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000204

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000452

Hom.:

Bravo

AF:

0.000181

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 02, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2022	Has not been previously published as pathogenic or benign to our knowledge; Frameshift variant predicted to result in protein truncation, as the last 229 amino acids are replaced with 2 different amino acids -

Hyperphosphatasia with intellectual disability syndrome 5

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2022	This sequence change creates a premature translational stop signal (p.Val206Glyfs*3) in the PIGW gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 299 amino acid(s) of the PIGW protein. This variant is present in population databases (rs753385776, gnomAD 0.09%). 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: 377301). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2022

The c.617_620delTTTG (p.V206Gfs*3) alteration, located in exon 2 (coding exon 1) of the PIGW gene, consists of a deletion of 4 nucleotides from position 617 to 620, causing a translational frameshift with a predicted alternate stop codon after 3 amino acids. This alteration occurs at the 3' terminus of the PIGW gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 299 amino acids of the protein. Premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, the c.617_620delTTTG allele has an overall frequency of 0.02% (69/282804) total alleles studied. The highest observed frequency was 0.08% (29/35438) of Latino alleles. Based on the available evidence, this alteration is classified as pathogenic. -

Global developmental delay;C2981150:Cleft palate;C4023165:Abnormal skeletal morphology

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Dec 03, 2018

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 03, 2023

Variant summary: PIGW c.617_620delTTTG (p.Val206GlyfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. The variant allele was found at a frequency of 0.00025 in 251406 control chromosomes.To our knowledge, no occurrence of c.617_620delTTTG in individuals affected with Hyperphosphatasia With Mental Retardation Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=2), Likely Pathogenic (n=3) and Pathogenic (n=1). Based on the evidence outlined above and the fact that there is not enough evidence to establish loss-of-function as a mechanism of disease for this gene, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over