18-62045869-C-T

Position:

chr18-62045869-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_176787.5(PIGN):c.2783G>A(p.Ser928Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,613,826 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 3 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.952

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056847334).

BP6

Variant 18-62045869-C-T is Benign according to our data. Variant chr18-62045869-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472229.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr18-62045869-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGN	NM_176787.5 linkuse as main transcript	c.2783G>A	p.Ser928Asn	missense_variant	31/31	ENST00000640252.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGN	ENST00000640252.2 linkuse as main transcript	c.2783G>A	p.Ser928Asn	missense_variant	31/31	1	NM_176787.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00106

AC:

161

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00612

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000871

AC:

217

AN:

249112

Hom.:

AF XY:

0.000821

AC XY:

111

AN XY:

135142

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00539

Gnomad NFE exome

AF:

0.000797

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.00111

AC:

1628

AN:

1461494

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

783

AN XY:

727034

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00727

Gnomad4 NFE exome

AF:

0.00106

Gnomad4 OTH exome

AF:

0.000861

GnomAD4 genome

AF:

0.00106

AC:

161

AN:

152332

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00612

Gnomad4 NFE

AF:

0.00129

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000864

Hom.:

Bravo

AF:

0.000472

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000253

AC:

ESP6500EA

AF:

0.00108

AC:

ExAC

AF:

0.000926

AC:

112

EpiCase

AF:

0.000709

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2016

The p.S928N variant (also known as c.2783G>A), located in coding exon 28 of the PIGN gene, results from a G to A substitution at nucleotide position 2783. The serine at codon 928 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

PIGN-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 12, 2023

This variant is classified as likely 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

Benign

0.083

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.0090

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

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.84

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

M_CAP

Benign

0.0077

MetaRNN

Benign

0.0057

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

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

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.12

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

REVEL

Benign

0.021

Sift

Benign

0.47

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

Sift4G

Benign

0.51

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

Polyphen

0.0010

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

Vest4

0.093, 0.090

MVP

0.48

MPC

0.027

ClinPred

0.017

GERP RS

4.3

Varity_R

0.056

gMVP

0.10

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

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