rs376226764

chr18-62106797-G-Achr18-62106797-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_176787.5(PIGN):c.1759C>T(p.Arg587Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000243 in 1,603,330 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R587R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: PIGN NM_176787.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.61

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-62106797-G-A is Pathogenic according to our data. Variant chr18-62106797-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 581123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGN	NM_176787.5	c.1759C>T	p.Arg587Ter	stop_gained	19/31	ENST00000640252.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGN	ENST00000640252.2	c.1759C>T	p.Arg587Ter	stop_gained	19/31	1	NM_176787.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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

GnomAD3 exomes AF: 0.0000256 AC: 6 AN: 234616 Hom.: 0 AF XY: 0.0000236 AC XY: 3 AN XY: 126908

Gnomad AFR exome AF: 0.0000706

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000233

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000950

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000255 AC: 37 AN: 1451260 Hom.: 0 Cov.: 28 AF XY: 0.0000180 AC XY: 13 AN XY: 721094

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000280

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000217

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74274

Gnomad4 AFR AF: 0.0000242

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: 0.0000489 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 19, 2019	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	This sequence change creates a premature translational stop signal (p.Arg587*) in the PIGN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PIGN are known to be pathogenic (PMID: 24253414, 27038415). This variant is present in population databases (rs376226764, gnomAD 0.02%). 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: 581123). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 35179230, 31440721, 36322149, 33502061) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	PIGN: PVS1, PM2, PM3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	43
Dann	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	A;A
Vest4		0.86, 0.86
GERP RS		4.2

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

Other links and lift over

dbSNP: rs376226764; hg19: chr18-59774030;