chr18-62161187-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_176787.5(PIGN):c.167C>T(p.Ala56Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,613,728 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A56T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 34 hom., cov: 33)

Exomes 𝑓: 0.012 ( 178 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 9.94

Publications

7 publications found

Variant links:

Genes affected

PIGN (HGNC:8967): (phosphatidylinositol glycan anchor biosynthesis class N) This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This protein is expressed in the endoplasmic reticulum and transfers phosphoethanolamine (EtNP) to the first mannose of the GPI anchor. Two alternatively spliced variants, which encode an identical isoform, have been reported. [provided by RefSeq, Jul 2008]

PIGN Gene-Disease associations (from GenCC):

multiple congenital anomalies-hypotonia-seizures syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet, ClinGen, PanelApp Australia
Fryns syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PIGN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.011676133).

BP6

Variant 18-62161187-G-A is Benign according to our data. Variant chr18-62161187-G-A is described in ClinVar as Benign. ClinVar VariationId is 447939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0106 (1620/152288) while in subpopulation NFE AF = 0.0125 (847/68028). AF 95% confidence interval is 0.0118. There are 34 homozygotes in GnomAd4. There are 924 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5 link	c.167C>T	p.Ala56Val	missense_variant	Exon 4 of 31	ENST00000640252.2	NP_789744.1	O95427A0A024R2C3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PIGN	ENST00000640252.2 link	c.167C>T	p.Ala56Val	missense_variant	Exon 4 of 31	1	NM_176787.5	ENSP00000492233.1	O95427
PIGN	ENST00000400334.7 link	c.167C>T	p.Ala56Val	missense_variant	Exon 3 of 30	1		ENSP00000383188.2	O95427
PIGN	ENST00000638424.1 link	n.167C>T		non_coding_transcript_exon_variant	Exon 2 of 29	5		ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes

AF:

0.0107

AC:

1621

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0558

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0124

Gnomad OTH

AF:

0.00910

GnomAD2 exomes

AF:

0.0123

AC:

3073

AN:

249062

AF XY:

0.0125

show subpopulations

Gnomad AFR exome

AF:

0.00168

Gnomad AMR exome

AF:

0.00388

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0534

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.00994

GnomAD4 exome

AF:

0.0123

AC:

18007

AN:

1461440

Hom.:

178

Cov.:

AF XY:

0.0121

AC XY:

8792

AN XY:

727012

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

33480

American (AMR)

AF:

0.00400

AC:

179

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00214

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.00342

AC:

295

AN:

86246

European-Finnish (FIN)

AF:

0.0481

AC:

2566

AN:

53394

Middle Eastern (MID)

AF:

0.00641

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0128

AC:

14203

AN:

1111646

Other (OTH)

AF:

0.00994

AC:

600

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

815

1630

2446

3261

4076

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

522

1044

1566

2088

2610

<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:

0.0106

AC:

1620

AN:

152288

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

924

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00221

AC:

AN:

41566

American (AMR)

AF:

0.00314

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00290

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0558

AC:

592

AN:

10602

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0125

AC:

847

AN:

68028

Other (OTH)

AF:

0.00900

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

161

241

322

402

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:

0.0114

Hom.:

Bravo

AF:

0.00692

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00278

AC:

ESP6500EA

AF:

0.0127

AC:

106

ExAC

AF:

0.0120

AC:

1449

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0136

EpiControl

AF:

0.0130

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PIGN: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Jul 11, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jun 21, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PIGN-related disorder

Benign:1

Apr 23, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

T;.;T;T;T;.;.;.;.;T;.;.;T;.;T;.;.;.;.;.;.;.;.;.;T;T;T;.;T

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;.;.;.;.;.;D;.;D;.;D;D;.;D;D;D;D;.;.;D;D;D;D;D;.;D;D;D;D

MetaRNN

Benign

0.012

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.083

MutationAssessor

Pathogenic

3.1

M;.;M;M;M;.;.;.;.;M;.;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

9.9

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.8

.;.;.;D;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

.;.;.;D;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Uncertain

0.011

.;.;.;D;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.

Polyphen

1.0

D;.;D;D;D;.;.;.;.;D;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.31, 0.33

MPC

0.20

ClinPred

0.039

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.82

Mutation Taster

=95/5

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over