18-62154635-G-C

Position:

• chr18-62154635-G-C

Variant summary

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

The NM_176787.5(PIGN):​c.459C>G​(p.His153Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,972 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H153Y) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGN	NM_176787.5	c.459C>G	p.His153Gln	missense_variant	7/31	ENST00000640252.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGN	ENST00000640252.2	c.459C>G	p.His153Gln	missense_variant	7/31	1	NM_176787.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151972 Hom.: 0 Cov.: 33

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 22

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151972 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74214

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.20	T;.;T;T;T;.;.;.;.;T;.;.;T;.;T;.;.;.;.;.;.;.;.;.;T;T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	.;.;.;.;.;.;D;.;D;.;D;D;.;D;D;D;D;.;.;D;D;D;D;D;.;D;D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.51	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;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.2	M;.;M;M;M;.;.;.;.;M;.;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.4	.;.;.;D;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.46
Sift	Benign	0.071	.;.;.;T;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.057	.;.;.;T;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T
Polyphen		0.056	B;.;B;B;B;.;.;.;.;B;.;.;B;.;B;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.86
MutPred		0.47		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;
MVP		0.69
MPC		0.12
ClinPred		0.95	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs376615257; hg19: chr18-59821868;