rs762966799

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_176787.5(PIGN):c.1619C>T(p.Pro540Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000251 in 1,590,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.16

Publications

0 publications found

Variant links:

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

PIGN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1719982).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5 link	c.1619C>T	p.Pro540Leu	missense_variant	Exon 18 of 31	ENST00000640252.2	NP_789744.1	O95427A0A024R2C3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PIGN	ENST00000640252.2 link	c.1619C>T	p.Pro540Leu	missense_variant	Exon 18 of 31	1	NM_176787.5	ENSP00000492233.1	O95427
PIGN	ENST00000400334.7 link	c.1619C>T	p.Pro540Leu	missense_variant	Exon 17 of 30	1		ENSP00000383188.2	O95427
PIGN	ENST00000638424.1 link	n.1619C>T		non_coding_transcript_exon_variant	Exon 16 of 29	5		ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000467

AC:

AN:

214190

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000809

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1438508

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

713058

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32900

American (AMR)

AF:

0.00

AC:

AN:

41926

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25520

East Asian (EAS)

AF:

0.00

AC:

AN:

38618

South Asian (SAS)

AF:

0.00

AC:

AN:

81892

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100140

Other (OTH)

AF:

0.00

AC:

AN:

59660

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000833

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Uncertain:1

Jun 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 540 of the PIGN protein (p.Pro540Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PIGN-related conditions. ClinVar contains an entry for this variant (Variation ID: 472212). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PIGN protein function with a negative predictive value of 80%. 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

0.24

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.018

T;.;T;T;T;.;.;.;.;.;T;.;.;T;.;T;.;.

Eigen

Benign

0.0064

Eigen_PC

Benign

0.063

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

.;.;.;.;.;.;D;.;D;D;.;D;D;.;D;D;D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.17

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.4

M;.;M;M;M;.;.;.;.;.;M;.;.;M;.;M;.;.

PhyloP100

2.2

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.4

.;.;.;N;.;.;.;.;.;.;N;.;.;.;.;.;.;.

REVEL

Benign

0.16

Sift

Benign

0.71

.;.;.;T;.;.;.;.;.;.;T;.;.;.;.;.;.;.

Sift4G

Benign

0.27

.;.;.;T;.;.;.;.;.;.;T;.;.;.;.;.;.;.

Polyphen

0.43

B;.;B;B;B;.;.;.;.;.;B;.;.;B;.;B;.;.

Vest4

0.35, 0.36

MutPred

0.65

Loss of loop (P = 0.0203);.;Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);.;.;Loss of loop (P = 0.0203);.;.;Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);.;Loss of loop (P = 0.0203);.;Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);

MVP

0.75

MPC

0.033

ClinPred

0.17

GERP RS

5.2

Varity_R

0.070

gMVP

0.39

Mutation Taster

=63/37

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over