NM_176787.5:c.283C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

The NM_176787.5(PIGN):c.283C>T(p.Arg95Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,460,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R95Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 4.96

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-62157746-C-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.928

PP5

Variant 18-62157747-G-A is Pathogenic according to our data. Variant chr18-62157747-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 378361.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5 link	c.283C>T	p.Arg95Trp	missense_variant	Exon 5 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.283C>T	p.Arg95Trp	missense_variant	Exon 5 of 31	1	NM_176787.5	ENSP00000492233.1	O95427
PIGN	ENST00000400334.7 link	c.283C>T	p.Arg95Trp	missense_variant	Exon 4 of 30	1		ENSP00000383188.2	O95427
PIGN	ENST00000638424.1 link	n.283C>T		non_coding_transcript_exon_variant	Exon 3 of 29	5		ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1460066

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726192

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000387

Hom.:

Bravo

AF:

0.0000113

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Pathogenic:4

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PIGN related disorder (PMID: 26633542). A different missense change at the same codon (p.Arg95Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000648403 /PMID: 29096607 /3billion dataset). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

May 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 95 of the PIGN protein (p.Arg95Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with an abnormality of the nervous system and/or PIGN-related conditions (PMID: 26633542, 35179230, 35468813). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 378361). 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 expected to disrupt PIGN protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jan 23, 2020

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Pathogenic:1Uncertain:1

Oct 04, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 20, 2016

GeneDx

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

The R95W variant in the PIGN gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R95W variant was not observed in approximately 6100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R95W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R95W as a variant of uncertain significance. -

Inborn genetic diseases

Uncertain:1

Mar 28, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

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

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

1.0

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

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.38

MutationAssessor

Pathogenic

3.7

H;.;H;H;H;.;.;.;.;.;H;.;.;H;.;H;.;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-7.5

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

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.95

MVP

0.89

MPC

0.20

ClinPred

1.0

GERP RS

4.5

Varity_R

0.82

gMVP

0.96

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over