chr18-62045940-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_176787.5(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
NM_176787.5 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 was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5 link	c.2712T>G	p.Phe904Leu	missense_variant	Exon 31 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.2712T>G	p.Phe904Leu	missense_variant	Exon 31 of 31	1	NM_176787.5	ENSP00000492233.1	O95427
PIGN	ENST00000400334.7 link	c.2712T>G	p.Phe904Leu	missense_variant	Exon 30 of 30	1		ENSP00000383188.2	O95427
PIGN	ENST00000638424.1 link	n.*680T>G		non_coding_transcript_exon_variant	Exon 29 of 29	5		ENSP00000491963.1	A0A1W2PQZ1
PIGN	ENST00000638424.1 link	n.*680T>G		3_prime_UTR_variant	Exon 29 of 29	5		ENSP00000491963.1	A0A1W2PQZ1

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

GnomAD2 exomes

AF:

0.00937

AC:

2327

AN:

248306

AF XY:

0.00976

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 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

AC:

AN:

33472

Gnomad4 AMR exome

AF:

0.00459

AC:

205

AN:

44656

Gnomad4 ASJ exome

AF:

0.00479

AC:

125

AN:

26120

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39696

Gnomad4 SAS exome

AF:

0.00791

AC:

681

AN:

86110

Gnomad4 FIN exome

AF:

0.00562

AC:

300

AN:

53388

Gnomad4 NFE exome

AF:

0.0142

AC:

15818

AN:

1111514

Gnomad4 Remaining exome

AF:

0.00935

AC:

564

AN:

60350

Heterozygous variant carriers

789

1579

2368

3158

3947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

608

1216

1824

2432

3040

<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:

0.00831

AC:

1266

AN:

152310

Hom.:

Cov.:

AF XY:

0.00743

AC XY:

553

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00255

AC:

0.00254992

AN:

0.00254992

Gnomad4 AMR

AF:

0.00373

AC:

0.003725

AN:

0.003725

Gnomad4 ASJ

AF:

0.00432

AC:

0.00432028

AN:

0.00432028

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00663

AC:

0.00663075

AN:

0.00663075

Gnomad4 FIN

AF:

0.00320

AC:

0.0032003

AN:

0.0032003

Gnomad4 NFE

AF:

0.0144

AC:

0.0144075

AN:

0.0144075

Gnomad4 OTH

AF:

0.00710

AC:

0.00710227

AN:

0.00710227

Heterozygous variant carriers

124

186

248

310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0112

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

Apr 16, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 22, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PIGN: BP4, BS1, BS2 -

not specified

Benign:1

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

May 17, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

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

Mutation Taster

=88/12

polymorphism

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