rs368280915

Positions:

• chr18-62157713-T-C
• chr18-62157713-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_176787.5(PIGN):​c.317A>G​(p.Tyr106Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.89

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGN	NM_176787.5	c.317A>G	p.Tyr106Cys	missense_variant	5/31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.317A>G	p.Tyr106Cys	missense_variant	5/31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.317A>G	p.Tyr106Cys	missense_variant	4/30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.317A>G		non_coding_transcript_exon_variant	3/29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459662 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725866

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.;D;D;D;.;.;.;.;.;D;.;.;D;.;D;.;.;.;.;.;.;.;.;.;T;T;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	.;.;.;.;.;.;D;.;D;D;.;D;D;.;D;D;D;D;.;.;D;D;D;D;D;.;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.94	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;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.6	H;.;H;H;H;.;.;.;.;.;H;.;.;H;.;H;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-8.4	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Polyphen		1.0	D;.;D;D;D;.;.;.;.;.;D;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.98, 0.98
MutPred		0.82		Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);.;Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);Gain of catalytic residue at S110 (P = 0.0394);.;Gain of catalytic residue at S110 (P = 0.0394);
MVP		0.92
MPC		0.21
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.88
gMVP		0.95

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: rs368280915; hg19: chr18-59824946;