rs1060499763

Positions:

• chr18-62140447-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I332V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• 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]

ACMG classification

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: {Likely_pathogenic=4, Uncertain_significance=1, Pathogenic=1}. Variant chr18-62140447-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGN	NM_176787.5	c.996T>G	p.Ile332Met	missense_variant	12/31	ENST00000640252.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGN	ENST00000640252.2	c.996T>G	p.Ile332Met	missense_variant	12/31	1	NM_176787.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1403320 Hom.: 0 Cov.: 22 AF XY: 0.00000143 AC XY: 1 AN XY: 697096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000395

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.35e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	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	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

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not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 15, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26539891, 33619735, 36322149, 35179230) -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.047	T;T;T;T;.;.;.;T;.;T;.;T;.;.;.;.;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.2	M;M;M;M;.;.;.;M;.;M;.;M;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
Polyphen		1.0	D;D;D;D;.;.;.;D;.;D;.;D;.;.;.;.;.;.;.
Vest4		0.91, 0.91
MutPred		0.69		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		0.98	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

Other links and lift over

dbSNP: rs1060499763; hg19: chr18-59807680;