NM_176787.5:c.1004C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_176787.5(PIGN):c.1004C>T(p.Pro335Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000504 in 1,388,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P335P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 8.11

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5 link	c.1004C>T	p.Pro335Leu	missense_variant	Exon 12 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.1004C>T	p.Pro335Leu	missense_variant	Exon 12 of 31	1	NM_176787.5	ENSP00000492233.1	O95427
PIGN	ENST00000400334.7 link	c.1004C>T	p.Pro335Leu	missense_variant	Exon 11 of 30	1		ENSP00000383188.2	O95427
PIGN	ENST00000638424.1 link	n.1004C>T		non_coding_transcript_exon_variant	Exon 10 of 29	5		ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000504

AC:

AN:

1388454

Hom.:

Cov.:

AF XY:

0.00000870

AC XY:

AN XY:

689858

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31940

American (AMR)

AF:

0.00

AC:

AN:

40526

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25120

East Asian (EAS)

AF:

0.00

AC:

AN:

38484

South Asian (SAS)

AF:

0.00

AC:

AN:

79158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51762

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.00000662

AC:

AN:

1058096

Other (OTH)

AF:

0.00

AC:

AN:

57754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Uncertain:2

Dec 07, 2022

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2022

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 335 of the PIGN protein (p.Pro335Leu). This variant is not present in population databases (gnomAD no frequency). 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: 472204). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

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

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

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

M_CAP

Uncertain

0.088

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Pathogenic

3.2

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

PhyloP100

8.1

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-6.5

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

REVEL

Uncertain

0.54

Sift

Uncertain

0.017

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

Sift4G

Uncertain

0.015

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

Polyphen

1.0

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

Vest4

0.96, 0.96

MutPred

0.53

Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);.;Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);

MVP

0.78

MPC

0.20

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.44

gMVP

0.58

Mutation Taster

=37/63

disease causing

(source)

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

Publications

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NM_176787.5:c.1004C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over