Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_176787.5(PIGN):c.1240T>A(p.Phe414Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000513 in 1,364,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000051 ( 0 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.03

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176787.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIGN	NM_176787.5	MANE Select	c.1240T>A	p.Phe414Ile	missense	Exon 15 of 31	NP_789744.1
PIGN	NM_001438896.1		c.1240T>A	p.Phe414Ile	missense	Exon 15 of 32	NP_001425825.1
PIGN	NM_012327.6		c.1240T>A	p.Phe414Ile	missense	Exon 14 of 30	NP_036459.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIGN	ENST00000640252.2	TSL:1 MANE Select	c.1240T>A	p.Phe414Ile	missense	Exon 15 of 31	ENSP00000492233.1
PIGN	ENST00000400334.7	TSL:1	c.1240T>A	p.Phe414Ile	missense	Exon 14 of 30	ENSP00000383188.2
PIGN	ENST00000638424.1	TSL:5	n.1240T>A		non_coding_transcript_exon	Exon 13 of 29	ENSP00000491963.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000127

AC:

AN:

157092

AF XY:

0.0000121

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000513

AC:

AN:

1364770

Hom.:

Cov.:

AF XY:

0.00000888

AC XY:

AN XY:

675320

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31090

American (AMR)

AF:

0.00

AC:

AN:

35646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24926

East Asian (EAS)

AF:

0.00

AC:

AN:

35588

South Asian (SAS)

AF:

0.0000764

AC:

AN:

78574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5632

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1047394

Other (OTH)

AF:

0.0000176

AC:

AN:

56848

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ExAC

AF:

0.0000253

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Multiple congenital anomalies-hypotonia-seizures syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.26

Eigen

Benign

-0.088

Eigen_PC

Benign

-0.016

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PhyloP100

7.0

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-4.3

REVEL

Benign

0.23

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0090

Polyphen

0.040

Vest4

0.30

MutPred

0.66

Gain of helix (P = 0.0854)

MVP

0.49

MPC

0.035

ClinPred

0.89

GERP RS

4.9

Varity_R

0.25

gMVP

0.56

Mutation Taster

=48/52

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

18-62114572-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over