18-62140447-A-C
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_176787.5(PIGN):c.996T>G(p.Ile332Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000193 in 1,555,486 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
PIGN
NM_176787.5 missense
NM_176787.5 missense
Scores
2
8
9
Clinical Significance
Conservation
PhyloP100: 2.30
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 18-62140447-A-C is Pathogenic according to our data. Variant chr18-62140447-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 402190.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=3}. Variant chr18-62140447-A-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PIGN | NM_176787.5 | c.996T>G | p.Ile332Met | missense_variant | 12/31 | ENST00000640252.2 | NP_789744.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PIGN | ENST00000640252.2 | c.996T>G | p.Ile332Met | missense_variant | 12/31 | 1 | NM_176787.5 | ENSP00000492233.1 | ||
PIGN | ENST00000400334.7 | c.996T>G | p.Ile332Met | missense_variant | 11/30 | 1 | ENSP00000383188.2 | |||
PIGN | ENST00000638424.1 | n.996T>G | non_coding_transcript_exon_variant | 10/29 | 5 | ENSP00000491963.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
1
AN:
152166
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000143 AC: 2AN: 1403320Hom.: 0 Cov.: 22 AF XY: 0.00000143 AC XY: 1AN XY: 697096
GnomAD4 exome
AF:
AC:
2
AN:
1403320
Hom.:
Cov.:
22
AF XY:
AC XY:
1
AN XY:
697096
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
GnomAD4 genome
AF:
AC:
1
AN:
152166
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74338
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Multiple congenital anomalies-hypotonia-seizures syndrome 1 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 22, 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: 402190). This missense change has been observed in individual(s) with clinical features of PIGN congenital disorder of glycosylation (PMID: 26539891, 33619735, 35179230). 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 isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 332 of the PIGN protein (p.Ile332Met). - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Dec 06, 2017 | - - |
Abnormal brain morphology Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 10, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26539891, 33619735, 36322149, 35179230, 34540776) - |
PIGN-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 07, 2022 | The PIGN c.996T>G variant is predicted to result in the amino acid substitution p.Ile332Met. This variant has been reported in the homozygous and compound heterozygous state with a premature termination variant in two individuals with PIGN-related phenotypes (Karaca et al 2015. PubMed ID: 26539891, Sup Table 1A; Brunet T et al 2021. PubMed ID: 33619735, Supp Table). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (1 allele, http://gnomad.broadinstitute.org/variant/18-59807680-A-C), indicating it is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;T;T;.;.;.;T;.;T;.;T;.;.;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;.;.;.;D;.;D;.;D;.;D;D;D;D;.;.;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M;M;M;.;.;.;M;.;M;.;M;.;.;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
.;.;N;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.
REVEL
Benign
Sift
Uncertain
.;.;D;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Uncertain
.;.;D;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.
Polyphen
D;D;D;D;.;.;.;D;.;D;.;D;.;.;.;.;.;.;.
Vest4
0.91, 0.91
MutPred
Loss of stability (P = 0.0761);Loss of stability (P = 0.0761);Loss of stability (P = 0.0761);Loss of stability (P = 0.0761);Loss of stability (P = 0.0761);Loss of stability (P = 0.0761);.;Loss of stability (P = 0.0761);Loss of stability (P = 0.0761);Loss of stability (P = 0.0761);Loss of stability (P = 0.0761);Loss of stability (P = 0.0761);Loss of stability (P = 0.0761);Loss of stability (P = 0.0761);Loss of stability (P = 0.0761);Loss of stability (P = 0.0761);Loss of stability (P = 0.0761);Loss of stability (P = 0.0761);Loss of stability (P = 0.0761);
MVP
0.53
MPC
0.051
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at