rs932238722

Positions:

• chr18-62045959-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_176787.5(PIGN):​c.2693T>C​(p.Val898Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36407724).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGN	NM_176787.5	c.2693T>C	p.Val898Ala	missense_variant	31/31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.2693T>C	p.Val898Ala	missense_variant	31/31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.2693T>C	p.Val898Ala	missense_variant	30/30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.*661T>C		non_coding_transcript_exon_variant	29/29	5		ENSP00000491963.1
PIGN	ENST00000638424.1	n.*661T>C		3_prime_UTR_variant	29/29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 21, 2018

This sequence change replaces valine with alanine at codon 898 of the PIGN protein (p.Val898Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PIGN-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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	Uncertain	0.37
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.015	T;.;T;T;T;.;.;.;.;.;T;.;.;T;.;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	.;.;.;.;.;.;D;.;D;D;.;D;D;.;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.88	L;.;L;L;L;.;.;.;.;.;L;.;.;L;.;L
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.57	.;.;.;N;.;.;.;.;.;.;N;.;.;.;.;.
REVEL	Benign	0.21
Sift	Benign	1.0	.;.;.;T;.;.;.;.;.;.;T;.;.;.;.;.
Sift4G	Benign	0.50	.;.;.;T;.;.;.;.;.;.;T;.;.;.;.;.
Polyphen		0.90	P;.;P;P;P;.;.;.;.;.;P;.;.;P;.;P
Vest4		0.71, 0.70
MutPred		0.35		Loss of stability (P = 0.1466);.;Loss of stability (P = 0.1466);Loss of stability (P = 0.1466);Loss of stability (P = 0.1466);.;.;.;.;.;Loss of stability (P = 0.1466);.;.;Loss of stability (P = 0.1466);.;Loss of stability (P = 0.1466);
MVP		0.46
MPC		0.070
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.084
gMVP		0.46

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: rs932238722; hg19: chr18-59713192;