chr18-62154625-A-G

Position:

• chr18-62154625-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_176787.5(PIGN):​c.469T>C​(p.Tyr157His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.202

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.071731865).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGN	NM_176787.5	c.469T>C	p.Tyr157His	missense_variant	7/31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.469T>C	p.Tyr157His	missense_variant	7/31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.469T>C	p.Tyr157His	missense_variant	6/30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.469T>C		non_coding_transcript_exon_variant	5/29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1417600 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 707816

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jan 27, 2020

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. 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 histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PIGN-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with histidine at codon 157 of the PIGN protein (p.Tyr157His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.10
DANN	Benign	0.61
DEOGEN2	Benign	0.013	T;.;T;T;T;.;.;.;.;T;.;.;T;.;T;.;.;.;.;.;.;.;.;.;T;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.80	.;.;.;.;.;.;T;.;T;.;T;T;.;T;T;T;T;.;.;T;T;T;T;T;.;T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.072	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;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.65	N;.;N;N;N;.;.;.;.;N;.;.;N;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.70	.;.;.;N;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.15
Sift	Benign	0.61	.;.;.;T;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.69	.;.;.;T;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T
Polyphen		0.0	B;.;B;B;B;.;.;.;.;B;.;.;B;.;B;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.11, 0.11
MutPred		0.46		Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);.;Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);.;
MVP		0.45
MPC		0.026
ClinPred		0.035	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.041
gMVP		0.43

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: rs1555696260; hg19: chr18-59821858;