rs754047821

Variant names:

• chr18-62090568-G-A
• rs754047821
• NM_176787.5:c.2191C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-62090568-G-A
• chr18-62090568-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_176787.5(PIGN):​c.2191C>T​(p.Leu731Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L731V) 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: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40833712).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5	c.2191C>T	p.Leu731Phe	missense_variant	Exon 24 of 31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.2191C>T	p.Leu731Phe	missense_variant	Exon 24 of 31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.2191C>T	p.Leu731Phe	missense_variant	Exon 23 of 30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.2191C>T		non_coding_transcript_exon_variant	Exon 22 of 29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444786 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 719752

African (AFR) AF: 0.00 AC: 0 AN: 33128

American (AMR) AF: 0.00 AC: 0 AN: 44414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.00 AC: 0 AN: 39352

South Asian (SAS) AF: 0.00 AC: 0 AN: 85420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097768

Other (OTH) AF: 0.00 AC: 0 AN: 59760

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1 Uncertain:1

Apr 12, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine with phenylalanine at codon 731 of the PIGN protein (p.Leu731Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PIGN-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.;T;T;T;.;.;.;.;.;T;.;.;T;.;T;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	.;.;.;.;.;.;D;.;D;D;.;D;D;.;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.3	M;.;M;M;M;.;.;.;.;.;M;.;.;M;.;M;.;.
PhyloP100		2.0
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.3	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.
REVEL	Benign	0.26
Sift	Benign	0.031	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.
Sift4G	Uncertain	0.030	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.
Polyphen		0.73	P;.;P;P;P;.;.;.;.;.;P;.;.;P;.;P;.;.
Vest4		0.32, 0.32
MutPred		0.76		Gain of catalytic residue at L731 (P = 0.0067);.;Gain of catalytic residue at L731 (P = 0.0067);Gain of catalytic residue at L731 (P = 0.0067);Gain of catalytic residue at L731 (P = 0.0067);.;.;Gain of catalytic residue at L731 (P = 0.0067);.;.;Gain of catalytic residue at L731 (P = 0.0067);Gain of catalytic residue at L731 (P = 0.0067);.;Gain of catalytic residue at L731 (P = 0.0067);.;Gain of catalytic residue at L731 (P = 0.0067);Gain of catalytic residue at L731 (P = 0.0067);Gain of catalytic residue at L731 (P = 0.0067);
MVP		0.66
MPC		0.083
ClinPred		0.82	D
GERP RS		2.4
Varity_R		0.18
gMVP		0.41
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs754047821; hg19: chr18-59757801;