dbSNP rs587777187: PIGN:p.Gln321His (chr18-62143306-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001438896.1(PIGN):c.963G>C(p.Gln321His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000745 in 1,341,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q321Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

PIGN
NM_001438896.1 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.94

Publications

12 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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438896.1. 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.963G>C	p.Gln321His	missense splice_region	Exon 11 of 31	NP_789744.1
PIGN	NM_001438896.1		c.963G>C	p.Gln321His	missense splice_region	Exon 11 of 32	NP_001425825.1
PIGN	NM_012327.6		c.963G>C	p.Gln321His	missense splice_region	Exon 10 of 30	NP_036459.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIGN	ENST00000640252.2	TSL:1 MANE Select	c.963G>C	p.Gln321His	missense splice_region	Exon 11 of 31	ENSP00000492233.1
PIGN	ENST00000400334.7	TSL:1	c.963G>C	p.Gln321His	missense splice_region	Exon 10 of 30	ENSP00000383188.2
PIGN	ENST00000638424.1	TSL:5	n.963G>C		splice_region non_coding_transcript_exon	Exon 9 of 29	ENSP00000491963.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.45e-7

AC:

AN:

1341494

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

667804

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30890

American (AMR)

AF:

0.00

AC:

AN:

39616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24796

East Asian (EAS)

AF:

0.00

AC:

AN:

37644

South Asian (SAS)

AF:

0.00

AC:

AN:

78624

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50828

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5532

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1017294

Other (OTH)

AF:

0.00

AC:

AN:

56270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.040

MetaRNN

Pathogenic

0.90

MetaSVM

Benign

-0.46

MutationAssessor

Pathogenic

3.7

PhyloP100

5.9

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.81

Loss of stability (P = 0.2752)

MVP

0.80

MPC

0.19

ClinPred

1.0

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.91

Mutation Taster

=8/92

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.80

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.80

Position offset: 0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over