18-62113150-A-T

Variant names:

• chr18-62113150-A-T
• rs922043983
• NM_176787.5:c.1418T>A

Variant summary

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

The NM_176787.5(PIGN):​c.1418T>A​(p.Val473Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 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. V473I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.579
• 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.1418T>A	p.Val473Asp	missense_variant	Exon 16 of 31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.1418T>A	p.Val473Asp	missense_variant	Exon 16 of 31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.1418T>A	p.Val473Asp	missense_variant	Exon 15 of 30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.1418T>A		non_coding_transcript_exon_variant	Exon 14 of 29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456444 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724014

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 43924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25970

East Asian (EAS) AF: 0.00 AC: 0 AN: 39436

South Asian (SAS) AF: 0.00 AC: 0 AN: 85508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108992

Other (OTH) AF: 0.00 AC: 0 AN: 60244

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.82
DEOGEN2	Benign	0.010	T;.;T;T;T;.;.;.;.;T;.;.;T;T;.;.;.;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.10	N
LIST_S2	Uncertain	0.88	.;.;.;.;.;.;.;D;D;.;D;D;.;D;D;D;.;.;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	M;.;M;M;M;.;.;.;.;M;.;.;M;M;.;.;.;.;.
PhyloP100		0.58
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.85	.;.;.;N;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.085
Sift	Benign	0.41	.;.;.;T;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.63	.;.;.;T;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.
Polyphen		0.16	B;.;B;B;B;.;.;.;.;B;.;.;B;B;.;.;.;.;.
Vest4		0.37
MutPred		0.69		Gain of disorder (P = 0.0228);.;Gain of disorder (P = 0.0228);Gain of disorder (P = 0.0228);Gain of disorder (P = 0.0228);.;Gain of disorder (P = 0.0228);.;.;Gain of disorder (P = 0.0228);Gain of disorder (P = 0.0228);.;Gain of disorder (P = 0.0228);Gain of disorder (P = 0.0228);Gain of disorder (P = 0.0228);Gain of disorder (P = 0.0228);Gain of disorder (P = 0.0228);Gain of disorder (P = 0.0228);Gain of disorder (P = 0.0228);
MVP		0.35
MPC		0.040
ClinPred		0.094	T
GERP RS		-0.034
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.079
gMVP		0.43
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.29		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs922043983; hg19: chr18-59780383;