rs61755368

chr17-36537806-C-Gchr17-36537806-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001346754.2(PIGW):c.705C>G(p.His235Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00826 in 1,614,112 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H235R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0083 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (66 hom.)
• Consequence: PIGW NM_001346754.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.996

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014726132).
• BP6: Variant 17-36537806-C-G is Benign according to our data. Variant chr17-36537806-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 377070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00829 (1262/152294) while in subpopulation AMR AF= 0.0112 (172/15300). AF 95% confidence interval is 0.0105. There are 7 homozygotes in gnomad4. There are 668 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGW	NM_001346754.2	c.705C>G	p.His235Gln	missense_variant	2/2	ENST00000614443.2
PIGW	NM_001346755.2	c.705C>G	p.His235Gln	missense_variant	2/2
PIGW	NM_178517.5	c.705C>G	p.His235Gln	missense_variant	2/2
MYO19	XM_047436823.1	c.-295-3702G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGW	ENST00000614443.2	c.705C>G	p.His235Gln	missense_variant	2/2	1	NM_001346754.2	P1

Frequencies

GnomAD3 genomes AF: 0.00829 AC: 1262 AN: 152176 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00748 AC: 1875 AN: 250600 Hom.: 14 AF XY: 0.00717 AC XY: 974 AN XY: 135752

Gnomad AFR exome AF: 0.00165

Gnomad AMR exome AF: 0.00457

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0266

Gnomad NFE exome AF: 0.00917

Gnomad OTH exome AF: 0.00789

GnomAD4 exome AF: 0.00826 AC: 12078 AN: 1461818 Hom.: 66 Cov.: 32 AF XY: 0.00813 AC XY: 5915 AN XY: 727202

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00449

Gnomad4 ASJ exome AF: 0.00337

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.0244

Gnomad4 NFE exome AF: 0.00906

Gnomad4 OTH exome AF: 0.00616

GnomAD4 genome AF: 0.00829 AC: 1262 AN: 152294 Hom.: 7 Cov.: 32 AF XY: 0.00897 AC XY: 668 AN XY: 74458

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0245

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00557 Hom.: 7

Bravo AF: 0.00558

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00695 AC: 844

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00780

EpiControl AF: 0.00788

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PIGW: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2020	This variant is associated with the following publications: (PMID: 28327575) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 30, 2016	- -

Hyperphosphatasia with intellectual disability syndrome 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;.;T
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Uncertain	-0.057	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.95, 0.95
MutPred		0.92		Gain of catalytic residue at H235 (P = 0.1155);Gain of catalytic residue at H235 (P = 0.1155);Gain of catalytic residue at H235 (P = 0.1155);
MVP		0.40
ClinPred		0.067	T
GERP RS		2.7
Varity_R		0.27
gMVP		0.87

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: rs61755368; hg19: chr17-34893655;