rs779636222

Positions:

chr18-62154538-CACAAACCT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_176787.5(PIGN):c.548_549+6delAGGTTTGT(p.Lys183fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000325 in 1,345,956 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

PIGN
NM_176787.5 frameshift, splice_donor, splice_region, intron

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 8.36

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:

PIGN (HGNC:):

PIGN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 18-62154538-CACAAACCT-C is Pathogenic according to our data. Variant chr18-62154538-CACAAACCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 264637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-62154538-CACAAACCT-C is described in Lovd as [Pathogenic]. Variant chr18-62154538-CACAAACCT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGN	NM_176787.5 linkuse as main transcript	c.548_549+6delAGGTTTGT	p.Lys183fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	7/31	ENST00000640252.2	NP_789744.1	O95427A0A024R2C3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PIGN	ENST00000640252.2 linkuse as main transcript	c.548_549+6delAGGTTTGT	p.Lys183fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	7/31	1	NM_176787.5	ENSP00000492233.1	O95427
PIGN	ENST00000400334.7 linkuse as main transcript	c.548_549+6delAGGTTTGT	p.Lys183fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	6/30	1		ENSP00000383188.2	O95427
PIGN	ENST00000638424.1 linkuse as main transcript	n.548_549+6delAGGTTTGT		splice_donor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	5/29	5		ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

151714

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000130

AC:

AN:

245596

Hom.:

AF XY:

0.000143

AC XY:

AN XY:

133154

show subpopulations

Gnomad AFR exome

AF:

0.0000649

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000259

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000353

AC:

421

AN:

1194242

Hom.:

AF XY:

0.000318

AC XY:

193

AN XY:

607212

show subpopulations

Gnomad4 AFR exome

AF:

0.0000709

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000463

Gnomad4 OTH exome

AF:

0.000311

GnomAD4 genome

AF:

0.000105

AC:

AN:

151714

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74124

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.000136

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jan 25, 2024	This PIGN variant (rs779636222) is rare (<0.1%) in a large population dataset (gnomAD: 36/276898 total alleles; 0.013%; no homozygotes) and has an entry in ClinVar. It has been reported in one individual with multiple congenital anomalies-hypotonia-seizures syndrome in a compound heterozygous state with another pathogenic variant. This 8-bp deletion (ACAAACCT) covers two coding nucleotides and six intronic nucleotides, including the canonical splice donor site and is predicted to cause aberrant pre-mRNA splicing. We consider c.548_549+6del to be pathogenic for autosomal recessive multiple congenital anomalies-hypotonia-seizures syndrome-1. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This variant results in the deletion of part of exon 7 (c.548_549+6del) of the PIGN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PIGN are known to be pathogenic (PMID: 24253414, 27038415). This variant is present in population databases (rs779636222, gnomAD 0.03%). This variant has been observed in individual(s) with clinical features of multiple congenital anomalies-hypotonia-seizures syndrome (PMID: 26394714, 30293990, 30609409). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 264637). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 23, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 28, 2016	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2022	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27038415, 24253414, 26394714, 30609409, 30293990) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2018

The c.548_549+6delAGGTTTGT pathogenic mutation, located at the 3' end of coding exon 4 in the PIGN gene, results from a deletion of 2 coding nucleotides and 6 intronic nucleotides at positions c.548 to c.549+6, including the canonical donor site. In one study, this mutation was detected in an individual with multiple congenital anomalies-hypotonia-seizures syndrome who also carried a second PIGN alteration in trans (a gross deletion encompassing multiple exons) (Fleming, L. 2016. Am. J. Med. Genet. A 2016 Jan;170A(1):77-86). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Multiple congenital anomalies-hypotonia-seizures syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 10, 2016

The c.548_549+6delAGGTTTGT variant in PIGN has been reported in one patient with multiple congenital anomalies-hypotonia-seizures syndrome in a compound heteroz ygous state (Fleming 2016) and has been identified in 13/120594 chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enou gh to be consistent with a recessive carrier frequency. This deletion encompasse s the invariant region (+/- 1,2) of the splice consensus sequence and is predict ed to cause altered splicing leading to an abnormal or absent protein. Biallelic loss of function of the PIGN gene has been associated with multiple congenital anomalies-hypotonia-seizures syndrome. In summary, although additional studies a re required to fully establish its clinical significance, the c.548_549+6del var iant in PIGN is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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