rs149740779

chr20-45420368-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_015937.6(PIGT):c.806C>T(p.Thr269Met) variant causes a missense change. The variant allele was found at a frequency of 0.00107 in 1,613,680 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

PIGT
NM_015937.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.47

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.039145052).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000703 (107/152212) while in subpopulation NFE AF= 0.00121 (82/68028). AF 95% confidence interval is 0.000995. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGT	NM_015937.6 linkuse as main transcript	c.806C>T	p.Thr269Met	missense_variant	7/12	ENST00000279036.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGT	ENST00000279036.12 linkuse as main transcript	c.806C>T	p.Thr269Met	missense_variant	7/12	1	NM_015937.6	P1	Q969N2-1

Frequencies

GnomAD3 genomes

AF:

0.000704

AC:

107

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

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:

0.00121

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000527

AC:

132

AN:

250380

Hom.:

AF XY:

0.000465

AC XY:

AN XY:

135344

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000656

Gnomad FIN exome

AF:

0.0000469

Gnomad NFE exome

AF:

0.000997

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.00111

AC:

1618

AN:

1461468

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

773

AN XY:

727004

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000563

Gnomad4 NFE exome

AF:

0.00138

Gnomad4 OTH exome

AF:

0.000778

GnomAD4 genome

AF:

0.000703

AC:

107

AN:

152212

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00121

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000871

Hom.:

Bravo

AF:

0.000710

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000544

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.00119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Multiple congenital anomalies-hypotonia-seizures syndrome 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 269 of the PIGT protein (p.Thr269Met). This variant is present in population databases (rs149740779, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PIGT-related conditions. ClinVar contains an entry for this variant (Variation ID: 377166). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PIGT protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.0

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.023

T;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.024

MetaRNN

Benign

0.039

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.9

L;.;.;L;.;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.1

N;N;N;N;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.17

Sift

Benign

0.12

T;T;T;T;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.15

T;T;T;T;.;.;.;.;.;.;.;.;.;.;.

Polyphen

1.0

D;P;.;.;.;.;.;.;.;.;.;.;.;D;.

Vest4

0.78

MVP

0.58

MPC

0.58

ClinPred

0.13

GERP RS

5.4

Varity_R

0.15

gMVP

0.35

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