rs1555696260

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.469T>C(p.Tyr157His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Synonymous variant affecting the same amino acid position (i.e. Y157Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.202

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=0.071731865).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5 link	c.469T>C	p.Tyr157His	missense_variant	Exon 7 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.469T>C	p.Tyr157His	missense_variant	Exon 7 of 31	1	NM_176787.5	ENSP00000492233.1	O95427
PIGN	ENST00000400334.7 link	c.469T>C	p.Tyr157His	missense_variant	Exon 6 of 30	1		ENSP00000383188.2	O95427
PIGN	ENST00000638424.1 link	n.469T>C		non_coding_transcript_exon_variant	Exon 5 of 29	5		ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1417600

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707816

African (AFR)

AF:

0.00

AC:

AN:

32480

American (AMR)

AF:

0.00

AC:

AN:

44510

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25846

East Asian (EAS)

AF:

0.00

AC:

AN:

39360

South Asian (SAS)

AF:

0.00

AC:

AN:

84838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1073730

Other (OTH)

AF:

0.00

AC:

AN:

58802

GnomAD4 genome

Cov.:

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

Jan 27, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine 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. This variant has not been reported in the literature in individuals with PIGN-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with histidine at codon 157 of the PIGN protein (p.Tyr157His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.10

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.013

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

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.80

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

M_CAP

Benign

0.0085

MetaRNN

Benign

0.072

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.65

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

PhyloP100

-0.20

PrimateAI

Benign

0.30

PROVEAN

Benign

0.70

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

REVEL

Benign

0.15

Sift

Benign

0.61

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

Sift4G

Benign

0.69

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

Polyphen

0.0

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

Vest4

0.11, 0.11

MutPred

0.46

Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);.;Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);.;

MVP

0.45

MPC

0.026

ClinPred

0.035

GERP RS

-12

PromoterAI

0.017

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.041

gMVP

0.43

Mutation Taster

=95/5

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over