Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.996

Publications

12 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIGW	NM_001346754.2	MANE Select	c.705C>G	p.His235Gln	missense	Exon 2 of 2	NP_001333683.1
PIGW	NM_001346755.2		c.705C>G	p.His235Gln	missense	Exon 2 of 2	NP_001333684.1
PIGW	NM_178517.5		c.705C>G	p.His235Gln	missense	Exon 2 of 2	NP_848612.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIGW	ENST00000614443.2	TSL:1 MANE Select	c.705C>G	p.His235Gln	missense	Exon 2 of 2	ENSP00000482202.1
PIGW	ENST00000619326.1	TSL:1	c.705C>G	p.His235Gln	missense	Exon 2 of 2	ENSP00000480475.1
PIGW	ENST00000620233.1	TSL:2	c.705C>G	p.His235Gln	missense	Exon 2 of 2	ENSP00000480021.1

Frequencies

GnomAD3 genomes

AF:

0.00829

AC:

1262

AN:

152176

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00748

AC:

1875

AN:

250600

AF XY:

0.00717

show subpopulations

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 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.:

Cov.:

AF XY:

0.00813

AC XY:

5915

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33478

American (AMR)

AF:

0.00449

AC:

201

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00337

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0244

AC:

1301

AN:

53380

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00906

AC:

10071

AN:

1111986

Other (OTH)

AF:

0.00616

AC:

372

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

773

1546

2318

3091

3864

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

340

680

1020

1360

1700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00829

AC:

1262

AN:

152294

Hom.:

Cov.:

AF XY:

0.00897

AC XY:

668

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41560

American (AMR)

AF:

0.0112

AC:

172

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0245

AC:

260

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0112

AC:

760

AN:

68024

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00485

Hom.:

Bravo

AF:

0.00558

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00698

AC:

ExAC

AF:

0.00695

AC:

844

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00780

EpiControl

AF:

0.00788

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Hyperphosphatasia with intellectual disability syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Pathogenic

0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.015

MetaSVM

Uncertain

-0.057

MutationAssessor

Pathogenic

3.7

PhyloP100

1.0

PrimateAI

Uncertain

0.65

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.92

Gain of catalytic residue at H235 (P = 0.1155)

MVP

0.40

ClinPred

0.067

GERP RS

2.7

Varity_R

0.27

gMVP

0.87

Mutation Taster

=96/4

polymorphism

(source)

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

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rs61755368

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over