18-62148234-A-C

Position:

chr18-62148234-A-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_176787.5(PIGN):c.654T>G(p.His218Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000194 in 1,544,482 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 Likely pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.77

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 Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

PP5

Variant 18-62148234-A-C is Pathogenic according to our data. Variant chr18-62148234-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 539554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGN	NM_176787.5 linkuse as main transcript	c.654T>G	p.His218Gln	missense_variant	8/31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2 linkuse as main transcript	c.654T>G	p.His218Gln	missense_variant	8/31	1	NM_176787.5	ENSP00000492233	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152134

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

GnomAD3 exomes

AF:

0.0000252

AC:

AN:

158460

Hom.:

AF XY:

0.0000359

AC XY:

AN XY:

83628

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000630

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000201

AC:

AN:

1392348

Hom.:

Cov.:

AF XY:

0.0000189

AC XY:

AN XY:

686640

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:

0.0000251

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

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:

0.0000496

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 01, 2024	Variant summary: PIGN c.654T>G (p.His218Gln) results in a non-conservative amino acid change located in the GPI ethanolamine phosphate transferase 1, N-terminal (IPR037671) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 158460 control chromosomes. c.654T>G has been reported in the literature in individuals affected with Multiple Congenital Anomalies-Hypotonia Syndrome 1 (Bayat_2022, Denomm-Pichon_2022, Quinlan-Jones_2019, Brunet_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35179230, 33619735, 34782754, 30293990). ClinVar contains an entry for this variant (Variation ID: 539554). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 31, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 08, 2023	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. 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. ClinVar contains an entry for this variant (Variation ID: 539554). This missense change has been observed in individual(s) with clinical features of PIGN-congenital disorder of glycosylation (PMID: 351792, 30293990, 33619735, 34782754). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 218 of the PIGN protein (p.His218Gln). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	-	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 30, 2022

Reported with a second variant in the PIGN gene in a patient with epilepsy, developmental delay, and hypotonia in the published literature; however, segregation information was not provided (Bayat et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35179230, 33619735, 30293990) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

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

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.96

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

Pathogenic

0.88

MutationAssessor

Pathogenic

3.7

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

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-7.8

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

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.99

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

Vest4

0.90, 0.90

MutPred

0.82

Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);.;.;Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);Loss of catalytic residue at H218 (P = 0.1002);

MVP

0.94

MPC

0.20

ClinPred

1.0

GERP RS

4.7

Varity_R

0.97

gMVP

0.85

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