rs768633670

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_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

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 55
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
multiple congenital anomalies-hypotonia-seizures syndrome
Inheritance: AR Classification: MODERATE Submitted by: G2P
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PIGP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 78 codons. Genomic position: 37067304. Lost 0.573 part of the original CDS.

PP5

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

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGP	ENST00000360525.9 link	c.2T>C	p.Met1?	start_lost	Exon 2 of 5	1	NM_153682.3	ENSP00000353719.3

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

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251494

AF XY:

0.0000294

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 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

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000935

AC:

104

AN:

1111992

Other (OTH)

AF:

0.0000662

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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

AF:

0.0000394

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

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

Nov 11, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 28, 2019

Mendelics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 14, 2022

DASA

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Nov 23, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderate, PM3 moderate, PP1 supporting -

PIGP-related disorder

Pathogenic:1

Aug 12, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Mar 10, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

not provided

Pathogenic:1

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Developmental and epileptic encephalopathy

Uncertain:1

Feb 23, 2017

Care4Rare-SOLVE, CHEO

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

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

(source)

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;.;.

PhyloP100

7.3

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

PromoterAI

-0.086

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.69

gMVP

0.91

Mutation Taster

=3/197

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over