rs377036162

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_176787.5(PIGN):c.884G>T(p.Arg295Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,607,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R295S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: -0.120

Publications

0 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0506441).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5 link	c.884G>T	p.Arg295Ile	missense_variant	Exon 10 of 31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PIGN	ENST00000640252.2 link	c.884G>T	p.Arg295Ile	missense_variant	Exon 10 of 31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7 link	c.884G>T	p.Arg295Ile	missense_variant	Exon 9 of 30	1		ENSP00000383188.2
PIGN	ENST00000638424.1 link	n.884G>T		non_coding_transcript_exon_variant	Exon 8 of 29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000221

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.0000807

AC:

AN:

247804

AF XY:

0.0000744

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.0000878

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000106

AC:

154

AN:

1455410

Hom.:

Cov.:

AF XY:

0.0000856

AC XY:

AN XY:

724196

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33342

American (AMR)

AF:

0.000157

AC:

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26046

East Asian (EAS)

AF:

0.00

AC:

AN:

39552

South Asian (SAS)

AF:

0.00

AC:

AN:

85694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.000126

AC:

140

AN:

1107010

Other (OTH)

AF:

0.0000998

AC:

AN:

60122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000112

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68026

Other (OTH)

AF:

0.000955

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000575

Hom.:

Bravo

AF:

0.000140

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000245

AC:

ExAC

AF:

0.000108

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Uncertain:2

Mar 19, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 295 of the PIGN protein (p.Arg295Ile). This variant is present in population databases (rs377036162, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PIGN-related conditions. ClinVar contains an entry for this variant (Variation ID: 472237). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PIGN protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Aug 01, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.884G>T (p.R295I) alteration is located in exon 10 (coding exon 7) of the PIGN gene. This alteration results from a G to T substitution at nucleotide position 884, causing the arginine (R) at amino acid position 295 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jul 20, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.011

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

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.87

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

M_CAP

Benign

0.016

MetaRNN

Benign

0.051

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

Benign

-1.0

MutationAssessor

Benign

1.4

L;.;L;L;L;.;.;.;.;.;L;.;.;L;.;L;.;.;.;.;.;.;.;.

PhyloP100

-0.12

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.2

.;.;.;N;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.026

Sift

Benign

0.15

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

Sift4G

Benign

0.19

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

Polyphen

0.010

B;.;B;B;B;.;.;.;.;.;B;.;.;B;.;B;.;.;.;.;.;.;.;.

Vest4

0.20

MVP

0.39

MPC

0.039

ClinPred

0.021

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.035

gMVP

0.47

Mutation Taster

=90/10

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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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