21-37072514-A-G

Position:

chr21-37072514-A-G

Variant summary

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

The NM_153682.3(PIGP):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

PIGP
NM_153682.3 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:1

Conservation

PhyloP100: 7.28

Variant links:

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]

PIGP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 21-37072514-A-G is Pathogenic according to our data. Variant chr21-37072514-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 397551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-37072514-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGP	NM_153682.3 link	c.2T>C	p.Met1?	start_lost	2/5	ENST00000360525.9	NP_710149.1	P57054-2
PIGP	NM_001320480.2 link	c.2T>C	p.Met1?	start_lost	2/5		NP_001307409.1	P57054-2
PIGP	NM_153681.2 link	c.74T>C	p.Met25Thr	missense_variant	1/4		NP_710148.1	P57054-1
PIGP	NM_016430.4 link	c.-243T>C		5_prime_UTR_variant	2/6		NP_057514.2	P57054-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGP	ENST00000360525.9 link	c.2T>C	p.Met1?	start_lost	2/5	1	NM_153682.3	ENSP00000353719.3		P57054-2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251494

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.0000527

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000773

AC:

113

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000894

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:

0.0000935

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000767

Hom.:

Bravo

AF:

0.0000680

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 55

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 14, 2022	The c.2T>C;p.(Met1?) is a start-loss variant in the PIGP gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript -PVS1_supporting. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 28334793) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 397551; PMID: 28334793; 32042915; 31139695) - PS4. The variant is present at low allele frequencies population databases (rs768633670 - gnomAD 0.0003943%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Met1?) was detected in trans with a pathogenic variant (PMID: 28334793; 32042915) - PM3. In summary, the currently available evidence indicates that the variant is likely pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 11, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 23, 2021	ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderate, PM3 moderate, PP1 supporting -

PIGP-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 12, 2024

The PIGP c.2T>C variant is predicted to disrupt the translation initiation site (Start loss). This variant has been reported in the compound heterozygous state and to segregate with disease in four individuals from two families affected with PIGP-related disorders (Johnstone et al. 2017. PubMed ID: 28334793; Martín-Grau C et al. 2023. PubMed ID: 37125481). Functional studies in vitro indicate that this variant impacts protein function through reduced PIGP protein expression and reduced cell surface expression of GPI-anchored proteins (Johnstone et al. 2017. PubMed ID: 28334793). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. Based on the available evidence, we classify this variant as likely pathogenic. -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Mar 10, 2020

ACMG classification criteria: PS3, PS4, PM2, PM3 -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 15, 2023

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 25 of the PIGP protein (p.Met25Thr). This variant is present in population databases (rs768633670, gnomAD 0.006%). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 28334793). 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. ClinVar contains an entry for this variant (Variation ID: 397551). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change 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.456delA. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

.;T;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.43

.;T;.;D

M_CAP

Benign

0.043

MetaRNN

Pathogenic

0.77

D;D;D;D

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.97

.;L;.;.

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-2.3

N;D;N;N

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0020

D;T;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.92

MVP

0.51

MPC

0.045

ClinPred

0.85

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.69

gMVP

0.91

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