18-62106862-C-T

Position:

• chr18-62106862-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_176787.5(PIGN):​c.1694G>A​(p.Arg565His) variant causes a missense change. The variant allele was found at a frequency of 0.00013 in 1,608,100 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.18

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a topological_domain Lumenal (size 0) in uniprot entity PIGN_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGN	NM_176787.5	c.1694G>A	p.Arg565His	missense_variant	19/31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.1694G>A	p.Arg565His	missense_variant	19/31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.1694G>A	p.Arg565His	missense_variant	18/30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.1694G>A		non_coding_transcript_exon_variant	17/29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 151966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000960 AC: 23 AN: 239518 Hom.: 0 AF XY: 0.000123 AC XY: 16 AN XY: 129606

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000595

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000103

Gnomad FIN exome AF: 0.0000472

Gnomad NFE exome AF: 0.000130

Gnomad OTH exome AF: 0.000511

GnomAD4 exome AF: 0.000135 AC: 197 AN: 1456016 Hom.: 0 Cov.: 31 AF XY: 0.000140 AC XY: 101 AN XY: 723616

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000908

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000707

Gnomad4 FIN exome AF: 0.000207

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74326

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000100 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000829 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 10, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 565 of the PIGN protein (p.Arg565His). This variant is present in population databases (rs201835155, gnomAD 0.01%). This missense change has been observed in individual(s) with PIGN-related disease (PMID: 32220244). ClinVar contains an entry for this variant (Variation ID: 472213). 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. 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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2016

The p.R565H variant (also known as c.1694G>A), located in coding exon 16 of the PIGN gene, results from a G to A substitution at nucleotide position 1694. The arginine at codon 565 is replaced by histidine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs201835155. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/11946) total alleles studied and 0.01% (1/8198) European American alleles. Allele frequency data for this nucleotide position is not currently available from the 1000 Genomes Project. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2020

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32220244) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	D;.;D;D;D;.;.;.;.;.;D;.;.;D;.;D;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;.;.;.;.;.;D;.;D;D;.;D;D;.;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.4	M;.;M;M;M;.;.;.;.;.;M;.;.;M;.;M;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.8	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.
Polyphen		1.0	D;.;D;D;D;.;.;.;.;.;D;.;.;D;.;D;.;.
Vest4		0.90
MVP		0.88
MPC		0.21
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.71
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201835155; hg19: chr18-59774095; COSMIC: COSV62949229; COSMIC: COSV62949229;