rs587777186

Positions:

• chr18-62146023-A-G
• chr18-62146023-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_176787.5(PIGN):​c.808T>C​(p.Ser270Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000154 in 1,297,314 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S270T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: PIGN NM_176787.5 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.74

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_176787.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-62146023-A-G is Pathogenic according to our data. Variant chr18-62146023-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 101047.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-62146023-A-G is described in Lovd as [Likely_pathogenic]. Variant chr18-62146023-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGN	NM_176787.5	c.808T>C	p.Ser270Pro	missense_variant, splice_region_variant	10/31	ENST00000640252.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGN	ENST00000640252.2	c.808T>C	p.Ser270Pro	missense_variant, splice_region_variant	10/31	1	NM_176787.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000154 AC: 2 AN: 1297314 Hom.: 0 Cov.: 18 AF XY: 0.00000307 AC XY: 2 AN XY: 650918

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000516

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2023	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 270 of the PIGN protein (p.Ser270Pro). This missense change has been observed in individual(s) with multiple congenital anomalies, hypotonia, and seizures (PMID: 24253414, 26419326). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PIGN function (PMID: 24253414). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 101047). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 20, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;T;T;T;.;.;.;.;.;T;.;.;T;.;T;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	.;.;.;.;.;.;D;.;D;T;.;T;D;.;D;T;T;T;.;.;D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.61	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	Benign	-0.77	T
MutationAssessor	Pathogenic	3.5	M;.;M;M;M;.;.;.;.;.;M;.;.;M;.;M;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-4.7	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0040	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.013	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.97	D;.;D;D;D;.;.;.;.;.;D;.;.;D;.;D;.;.;.;.;.;.;.;.;.
Vest4		0.51, 0.50
MutPred		0.48		Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);.;.;Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);Loss of glycosylation at S270 (P = 0.051);
MVP		0.62
MPC		0.18
ClinPred		0.96	D
GERP RS		0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
gMVP		0.82

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: rs587777186; hg19: chr18-59813256;