rs778073829

Variant names:

• chr17-36537108-G-A
• rs778073829
• NM_001346754.2:c.7G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001346754.2(PIGW):​c.7G>A​(p.Glu3Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,584,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PIGW NM_001346754.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.40
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09413329).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346754.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGW	NM_001346754.2	MANE Select	c.7G>A	p.Glu3Lys	missense	Exon 2 of 2	NP_001333683.1	Q7Z7B1
	PIGW	NM_001346755.2		c.7G>A	p.Glu3Lys	missense	Exon 2 of 2	NP_001333684.1	Q7Z7B1
	PIGW	NM_178517.5		c.7G>A	p.Glu3Lys	missense	Exon 2 of 2	NP_848612.2	Q7Z7B1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGW	ENST00000614443.2	TSL:1 MANE Select	c.7G>A	p.Glu3Lys	missense	Exon 2 of 2	ENSP00000482202.1	Q7Z7B1
	PIGW	ENST00000619326.1	TSL:1	c.7G>A	p.Glu3Lys	missense	Exon 2 of 2	ENSP00000480475.1	A0A087WWS9
	PIGW	ENST00000620233.1	TSL:2	c.7G>A	p.Glu3Lys	missense	Exon 2 of 2	ENSP00000480021.1	Q7Z7B1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000437 AC: 1 AN: 228732 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000353

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1432628 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 710866

African (AFR) AF: 0.00 AC: 0 AN: 31914

American (AMR) AF: 0.0000528 AC: 2 AN: 37852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24572

East Asian (EAS) AF: 0.00 AC: 0 AN: 39412

South Asian (SAS) AF: 0.00 AC: 0 AN: 81868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099416

Other (OTH) AF: 0.00 AC: 0 AN: 59066

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.4
PrimateAI	Benign	0.42	T
Sift4G	Benign	0.17	T
Polyphen		0.020	B
Vest4		0.19
MutPred		0.24		Loss of ubiquitination at K4 (P = 0.0142)
MVP		0.21
ClinPred		0.16	T
GERP RS		3.8
Varity_R		0.066
gMVP		0.17

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

Other links and lift over

dbSNP: rs778073829; hg19: chr17-34892957;