rs1310594802

chr18-62147004-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_176787.5(PIGN):c.772A>G(p.Ile258Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.723

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 0 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, 7 uncertain in NM_176787.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048663944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGN	NM_176787.5	c.772A>G	p.Ile258Val	missense_variant	9/31	ENST00000640252.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGN	ENST00000640252.2	c.772A>G	p.Ile258Val	missense_variant	9/31	1	NM_176787.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248484 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460060 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4 AN XY: 726402

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 26, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 258 of the PIGN protein (p.Ile258Val). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 472235). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	6.4
Dann	Benign	0.39
DEOGEN2	Benign	0.024	T;.;T;T;T;.;.;.;.;.;T;.;.;T;.;T;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.65	D
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.049	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.30	N;.;N;N;N;.;.;.;.;.;N;.;.;N;.;N;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.91	D;D
PrimateAI	Benign	0.31	T
Polyphen		0.0010	B;.;B;B;B;.;.;.;.;.;B;.;.;B;.;B;.;.;.;.;.;.;.;.;.
Vest4		0.28, 0.27
MutPred		0.48		Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);.;.;Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);Gain of catalytic residue at I258 (P = 0.0715);
MVP		0.33
MPC		0.023
ClinPred		0.038	T
GERP RS		-3.2
Varity_R		0.015
gMVP		0.33

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: rs1310594802; hg19: chr18-59814237;