rs778481061

chr21-37065602-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_153682.3(PIGP):c.384del(p.Glu129AsnfsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,612,974 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: PIGP NM_153682.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 1.04

Genes affected

PIGP (HGNC:3046): (phosphatidylinositol glycan anchor biosynthesis class P) This gene encodes an enzyme involved in the first step of glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells that serves to anchor proteins to the cell surface. The encoded protein is a component of the GPI-N-acetylglucosaminyltransferase complex that catalyzes the transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI). This gene is located in the Down Syndrome critical region on chromosome 21 and is a candidate for the pathogenesis of Down syndrome. This gene has multiple pseudogenes and is a member of the phosphatidylinositol glycan anchor biosynthesis gene family. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-37065602-CT-C is Pathogenic according to our data. Variant chr21-37065602-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 397552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-37065602-CT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGP	NM_153682.3	c.384del	p.Glu129AsnfsTer34	frameshift_variant	5/5	ENST00000360525.9
PIGP	NM_153681.2	c.456del	p.Glu153AsnfsTer34	frameshift_variant	4/4
PIGP	NM_001320480.2	c.384del	p.Glu129AsnfsTer34	frameshift_variant	5/5
PIGP	NM_016430.4	c.306del	p.Glu103AsnfsTer34	frameshift_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGP	ENST00000360525.9	c.384del	p.Glu129AsnfsTer34	frameshift_variant	5/5	1	NM_153682.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000280 AC: 7 AN: 249612 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135126

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000622

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1460834 Hom.: 0 Cov.: 30 AF XY: 0.0000275 AC XY: 20 AN XY: 726722

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000378

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74314

Gnomad4 AFR AF: 0.0000241

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: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000727 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 55 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Aug 10, 2022	The c.384del;p.(Glu129Asnfs*34) is a null frameshift variant (NMD) in the PIGP gene without sufficient information about prediction of nonsense mediated mRNA decay (NMD); it is present in a relevant exon to the transcript, and disrupts < 10% of the protein product – PVS1_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: ID: 397552; OMIM: 605938.0002; PMID: 32042915; 31139695; 28334793) - PS4. The variant is present at low allele frequencies population databases (rs778481061 – gnomAD 0.0003944%; ABraOM no frequency - https://abraom.ib.usp.br/) -PM2_supporting.The p.(Glu129Asnfs*34) was detected in trans with a pathogenic variant (PMID: 32042915; 31139695; 28334793) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 32042915) - PP1_moderate. In summary, the currently available evidence indicates that the variant is pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Oct 11, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	This sequence change results in a frameshift in the PIGP gene (p.Glu153Asnfs*34). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the PIGP protein and extend the protein by 27 additional amino acid residues. This variant is present in population databases (rs778481061, gnomAD 0.007%). This frameshift has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 28334793, 31139695, 32042915). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.384del. ClinVar contains an entry for this variant (Variation ID: 397552). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects PIGP function (PMID: 28334793). For these reasons, this variant has been classified as Pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, no assertion criteria provided

research

Care4Rare-SOLVE, CHEO

Feb 23, 2017

This variant was found in a compound heterozygous state with c.74T>C. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs778481061; hg19: chr21-38437902;