18-62045940-A-C

Position:

chr18-62045940-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000640252.2(PIGN):c.2712T>G(p.Phe904Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,384 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F904C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0083 ( 6 hom., cov: 32)

Exomes 𝑓: 0.012 ( 145 hom. )

Consequence

PIGN
ENST00000640252.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.753

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005876571).

BP6

Variant 18-62045940-A-C is Benign according to our data. Variant chr18-62045940-A-C is described in ClinVar as [Benign]. Clinvar id is 472226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-62045940-A-C is described in Lovd as [Benign]. Variant chr18-62045940-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00831 (1266/152310) while in subpopulation NFE AF= 0.0144 (980/68020). AF 95% confidence interval is 0.0137. There are 6 homozygotes in gnomad4. There are 553 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGN	NM_176787.5 linkuse as main transcript	c.2712T>G	p.Phe904Leu	missense_variant	31/31	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.2712T>G	p.Phe904Leu	missense_variant	31/31	1	NM_176787.5	ENSP00000492233	P1

Frequencies

GnomAD3 genomes

AF:

0.00832

AC:

1266

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00256

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00663

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0144

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.00937

AC:

2327

AN:

248306

Hom.:

AF XY:

0.00976

AC XY:

1315

AN XY:

134670

show subpopulations

Gnomad AFR exome

AF:

0.00208

Gnomad AMR exome

AF:

0.00433

Gnomad ASJ exome

AF:

0.00478

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00839

Gnomad FIN exome

AF:

0.00553

Gnomad NFE exome

AF:

0.0149

Gnomad OTH exome

AF:

0.00861

GnomAD4 exome

AF:

0.0122

AC:

17805

AN:

1461074

Hom.:

145

Cov.:

AF XY:

0.0120

AC XY:

8710

AN XY:

726762

show subpopulations

Gnomad4 AFR exome

AF:

0.00185

Gnomad4 AMR exome

AF:

0.00459

Gnomad4 ASJ exome

AF:

0.00479

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00791

Gnomad4 FIN exome

AF:

0.00562

Gnomad4 NFE exome

AF:

0.0142

Gnomad4 OTH exome

AF:

0.00935

GnomAD4 genome

AF:

0.00831

AC:

1266

AN:

152310

Hom.:

Cov.:

AF XY:

0.00743

AC XY:

553

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00255

Gnomad4 AMR

AF:

0.00373

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00663

Gnomad4 FIN

AF:

0.00320

Gnomad4 NFE

AF:

0.0144

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.0119

Hom.:

Bravo

AF:

0.00822

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00222

AC:

ESP6500EA

AF:

0.0127

AC:

107

ExAC

AF:

0.00995

AC:

1203

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 16, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PIGN: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

9.3

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

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

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.82

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

MetaRNN

Benign

0.0059

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

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.2

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

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-4.0

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

REVEL

Benign

0.093

Sift

Benign

0.097

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

Sift4G

Benign

0.28

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

Polyphen

0.024

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

Vest4

0.27, 0.33

MutPred

0.15

Loss of MoRF binding (P = 0.4134);.;Loss of MoRF binding (P = 0.4134);Loss of MoRF binding (P = 0.4134);Loss of MoRF binding (P = 0.4134);.;.;.;.;.;Loss of MoRF binding (P = 0.4134);.;.;Loss of MoRF binding (P = 0.4134);.;Loss of MoRF binding (P = 0.4134);

MVP

0.31

MPC

0.026

ClinPred

0.036

GERP RS

0.22

Varity_R

0.21

gMVP

0.25

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