chr18-62146023-A-T

Position:

chr18-62146023-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PM5BP4

The NM_176787.5(PIGN):c.808T>A(p.Ser270Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000483 in 1,449,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. S270P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000039 ( 0 hom. )

Consequence

PIGN
NM_176787.5 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.74

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_176787.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-62146023-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 101047.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.38426566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGN	NM_176787.5 linkuse as main transcript	c.808T>A	p.Ser270Thr	missense_variant, splice_region_variant	10/31	ENST00000640252.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGN	ENST00000640252.2 linkuse as main transcript	c.808T>A	p.Ser270Thr	missense_variant, splice_region_variant	10/31	1	NM_176787.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152198

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000385

AC:

AN:

1297314

Hom.:

Cov.:

AF XY:

0.00000154

AC XY:

AN XY:

650918

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000407

Gnomad4 OTH exome

AF:

0.0000184

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000279

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 270 of the PIGN protein (p.Ser270Thr). This variant is not present in population databases (gnomAD no frequency). 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: 1046983). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant disrupts the p.Ser270 amino acid residue in PIGN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24253414, 26419326). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.30

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

Eigen

Benign

-0.026

Eigen_PC

Benign

-0.070

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

.;.;.;.;.;.;D;.;T;T;.;T;T;.;D;T;T;T;.;.;D;D;D;D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.38

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

Benign

-1.0

MutationAssessor

Uncertain

2.8

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

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.7

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

REVEL

Benign

0.21

Sift

Uncertain

0.019

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

Sift4G

Benign

0.068

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

Polyphen

0.39

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

Vest4

0.17, 0.17

MutPred

0.48

Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);.;.;Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);Gain of phosphorylation at S270 (P = 0.0673);

MVP

0.52

MPC

0.035

ClinPred

0.71

GERP RS

0.22

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.63

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