17-36537106-C-T

Variant names:

• chr17-36537106-C-T
• rs376634596
• NM_001346754.2:c.5C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001346754.2(PIGW):​c.5C>T​(p.Ser2Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,431,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PIGW NM_001346754.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.55
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30332303).

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.5C>T	p.Ser2Phe	missense	Exon 2 of 2	NP_001333683.1	Q7Z7B1
	PIGW	NM_001346755.2		c.5C>T	p.Ser2Phe	missense	Exon 2 of 2	NP_001333684.1	Q7Z7B1
	PIGW	NM_178517.5		c.5C>T	p.Ser2Phe	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.5C>T	p.Ser2Phe	missense	Exon 2 of 2	ENSP00000482202.1	Q7Z7B1
	PIGW	ENST00000619326.1	TSL:1	c.5C>T	p.Ser2Phe	missense	Exon 2 of 2	ENSP00000480475.1	A0A087WWS9
	PIGW	ENST00000620233.1	TSL:2	c.5C>T	p.Ser2Phe	missense	Exon 2 of 2	ENSP00000480021.1	Q7Z7B1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1431322 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 710064

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31894

American (AMR) AF: 0.00 AC: 0 AN: 37698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24460

East Asian (EAS) AF: 0.00 AC: 0 AN: 39374

South Asian (SAS) AF: 0.00 AC: 0 AN: 81630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098774

Other (OTH) AF: 0.00 AC: 0 AN: 59018

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.026
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.5
PrimateAI	Uncertain	0.62	T
Sift4G	Benign	0.12	T
Polyphen		0.14	B
Vest4		0.14
MutPred		0.30		Gain of stability (P = 0.0144)
MVP		0.40
ClinPred		0.84	D
GERP RS		4.8
Varity_R		0.11
gMVP		0.24
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs376634596; hg19: chr17-34892955;