18-62045959-A-T

Variant names:

• chr18-62045959-A-T
• rs932238722
• NM_176787.5:c.2693T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_176787.5(PIGN):​c.2693T>A​(p.Val898Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,710 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. V898F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.39
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• multiple congenital anomalies-hypotonia-seizures syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet, ClinGen, PanelApp Australia
• Fryns syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5	c.2693T>A	p.Val898Asp	missense_variant	Exon 31 of 31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.2693T>A	p.Val898Asp	missense_variant	Exon 31 of 31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.2693T>A	p.Val898Asp	missense_variant	Exon 30 of 30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.*661T>A		non_coding_transcript_exon_variant	Exon 29 of 29	5		ENSP00000491963.1
PIGN	ENST00000638424.1	n.*661T>A		3_prime_UTR_variant	Exon 29 of 29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460710 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726464

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 85978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111392

Other (OTH) AF: 0.0000166 AC: 1 AN: 60342

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;T;T;T;.;.;.;.;.;T;.;.;T;.;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	.;.;.;.;.;.;D;.;D;D;.;D;D;.;D;D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.7	M;.;M;M;M;.;.;.;.;.;M;.;.;M;.;M
PhyloP100		7.4
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.7	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.
REVEL	Uncertain	0.43
Sift	Benign	0.049	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.
Sift4G	Uncertain	0.017	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.
Polyphen		0.99	D;.;D;D;D;.;.;.;.;.;D;.;.;D;.;D
Vest4		0.90, 0.90
MutPred		0.41		Loss of catalytic residue at Y895 (P = 0.1984);.;Loss of catalytic residue at Y895 (P = 0.1984);Loss of catalytic residue at Y895 (P = 0.1984);Loss of catalytic residue at Y895 (P = 0.1984);.;.;.;.;.;Loss of catalytic residue at Y895 (P = 0.1984);.;.;Loss of catalytic residue at Y895 (P = 0.1984);.;Loss of catalytic residue at Y895 (P = 0.1984);
MVP		0.63
MPC		0.22
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.58
gMVP		0.87
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs932238722; hg19: chr18-59713192;