18-62045967-A-T

Variant names:

• chr18-62045967-A-T
• rs760573255
• NM_176787.5:c.2685T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_176787.5(PIGN):​c.2685T>A​(p.Tyr895*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIGN NM_176787.5 stop_gained
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.0960
• 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 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0397 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• 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.2685T>A	p.Tyr895*	stop_gained	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.2685T>A	p.Tyr895*	stop_gained	Exon 31 of 31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.2685T>A	p.Tyr895*	stop_gained	Exon 30 of 30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.*653T>A		non_coding_transcript_exon_variant	Exon 29 of 29	5		ENSP00000491963.1
PIGN	ENST00000638424.1	n.*653T>A		3_prime_UTR_variant	Exon 29 of 29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Benign	0.0010
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.50	N
PhyloP100		-0.096
Vest4		0.76, 0.78
GERP RS		-5.9
Mutation Taster		=12/188	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs760573255; hg19: chr18-59713200;