chr18-62113140-T-A

Position:

chr18-62113140-T-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_176787.5(PIGN):c.1428A>T(p.Glu476Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,605,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.32

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009998977).

BP6

Variant 18-62113140-T-A is Benign according to our data. Variant chr18-62113140-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 539552.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGN	NM_176787.5 linkuse as main transcript	c.1428A>T	p.Glu476Asp	missense_variant	16/31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2 linkuse as main transcript	c.1428A>T	p.Glu476Asp	missense_variant	16/31	1	NM_176787.5	ENSP00000492233	P1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000207

AC:

AN:

236914

Hom.:

AF XY:

0.000195

AC XY:

AN XY:

128160

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00225

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000379

Gnomad NFE exome

AF:

0.000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000111

AC:

161

AN:

1452858

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

721942

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00201

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000189

Gnomad4 NFE exome

AF:

0.0000777

Gnomad4 OTH exome

AF:

0.000216

GnomAD4 genome

AF:

0.000125

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000345

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.000141

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2020

The c.1428A>T (p.E476D) alteration is located in exon 16 (coding exon 13) of the PIGN gene. This alteration results from an A to T substitution at nucleotide position 1428, causing the glutamic acid (E) at amino acid position 476 to be replaced by an aspartic acid (D). Based on data from the Genome Aggregation Database (gnomAD) database, the PIGN c.1428A>T alteration was observed in 0.02% (52/268304) of total alleles studied, with a frequency of 0.22% (22/10064) in the Ashkenazi Jewish subpopulation. This amino acid position is not well conserved in available vertebrate species. The p.E476D alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 18, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.57

CADD

Benign

9.3

DANN

Benign

0.93

DEOGEN2

Benign

0.010

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

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.70

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

M_CAP

Benign

0.0071

MetaRNN

Benign

0.010

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

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

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

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.30

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

REVEL

Benign

0.034

Sift

Benign

0.31

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

Sift4G

Benign

0.60

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

Polyphen

0.0010

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

Vest4

0.059

MutPred

0.44

Gain of ubiquitination at K471 (P = 0.1008);.;Gain of ubiquitination at K471 (P = 0.1008);Gain of ubiquitination at K471 (P = 0.1008);Gain of ubiquitination at K471 (P = 0.1008);.;Gain of ubiquitination at K471 (P = 0.1008);.;.;Gain of ubiquitination at K471 (P = 0.1008);Gain of ubiquitination at K471 (P = 0.1008);.;Gain of ubiquitination at K471 (P = 0.1008);Gain of ubiquitination at K471 (P = 0.1008);Gain of ubiquitination at K471 (P = 0.1008);Gain of ubiquitination at K471 (P = 0.1008);Gain of ubiquitination at K471 (P = 0.1008);Gain of ubiquitination at K471 (P = 0.1008);Gain of ubiquitination at K471 (P = 0.1008);

MVP

0.46

MPC

0.023

ClinPred

0.029

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.056

gMVP

0.14

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over