20-45418853-G-T

Position:

chr20-45418853-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_015937.6(PIGT):c.367G>T(p.Val123Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0074 in 1,613,926 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0076 ( 76 hom. )

Consequence

PIGT
NM_015937.6 missense, splice_region

Scores

Splicing: ADA: 0.9778

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 7.73

Variant links:

Genes affected

PIGT (HGNC:14938): (phosphatidylinositol glycan anchor biosynthesis class T) 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 an essential component of the multisubunit enzyme, GPI transamidase. GPI transamidase mediates GPI anchoring in the endoplasmic reticulum, by catalyzing the transfer of fully assembled GPI units to proteins. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

PIGT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 20-45418853-G-T is Benign according to our data. Variant chr20-45418853-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 252704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-45418853-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00597 (909/152300) while in subpopulation AMR AF= 0.00908 (139/15304). AF 95% confidence interval is 0.00785. There are 8 homozygotes in gnomad4. There are 435 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGT	NM_015937.6 linkuse as main transcript	c.367G>T	p.Val123Leu	missense_variant, splice_region_variant	3/12	ENST00000279036.12	NP_057021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGT	ENST00000279036.12 linkuse as main transcript	c.367G>T	p.Val123Leu	missense_variant, splice_region_variant	3/12	1	NM_015937.6	ENSP00000279036	P1	Q969N2-1

Frequencies

GnomAD3 genomes

AF:

0.00598

AC:

910

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.00549

Gnomad AMR

AF:

0.00909

Gnomad ASJ

AF:

0.0458

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00707

Gnomad OTH

AF:

0.00764

GnomAD3 exomes

AF:

0.00618

AC:

1553

AN:

251486

Hom.:

AF XY:

0.00602

AC XY:

818

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00535

Gnomad ASJ exome

AF:

0.0456

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000849

Gnomad FIN exome

AF:

0.00185

Gnomad NFE exome

AF:

0.00692

Gnomad OTH exome

AF:

0.00603

GnomAD4 exome

AF:

0.00755

AC:

11040

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00727

AC XY:

5283

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00514

Gnomad4 ASJ exome

AF:

0.0473

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000823

Gnomad4 FIN exome

AF:

0.00159

Gnomad4 NFE exome

AF:

0.00788

Gnomad4 OTH exome

AF:

0.0101

GnomAD4 genome

AF:

0.00597

AC:

909

AN:

152300

Hom.:

Cov.:

AF XY:

0.00584

AC XY:

435

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00188

Gnomad4 AMR

AF:

0.00908

Gnomad4 ASJ

AF:

0.0458

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00254

Gnomad4 NFE

AF:

0.00707

Gnomad4 OTH

AF:

0.00756

Alfa

AF:

0.00838

Hom.:

Bravo

AF:

0.00635

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00733

AC:

ExAC

AF:

0.00521

AC:

632

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00725

EpiControl

AF:

0.00830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PIGT: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 23, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2021	- -

Multiple congenital anomalies-hypotonia-seizures syndrome 3

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Oct 16, 2015

- -

PIGT-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.062

T;.;.;.;.;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

D;D;D;D;T;T

MetaRNN

Benign

0.0075

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-2.3

N;N;.;.;.;.

REVEL

Benign

0.17

Sift

Uncertain

0.0070

D;D;.;.;.;.

Sift4G

Uncertain

0.014

D;D;.;.;.;.

Polyphen

0.11

B;.;.;.;.;.

Vest4

0.76

MutPred

0.76

Loss of methylation at K128 (P = 0.084);Loss of methylation at K128 (P = 0.084);Loss of methylation at K128 (P = 0.084);Loss of methylation at K128 (P = 0.084);.;Loss of methylation at K128 (P = 0.084);

MVP

0.32

MPC

0.26

ClinPred

0.022

GERP RS

5.8

Varity_R

0.32

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.85

SpliceAI score (max)

0.030

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