17-16299889-G-T

Position:

chr17-16299889-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBS1_SupportingBS2

The NM_004278.4(PIGL):c.337G>T(p.Asp113Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,611,988 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

PIGL
NM_004278.4 missense, splice_region

Scores

Splicing: ADA: 0.0001387

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 0.504

Variant links:

Genes affected

PIGL (HGNC:8966): (phosphatidylinositol glycan anchor biosynthesis class L) This gene encodes an enzyme that catalyzes the second step of glycosylphosphatidylinositol (GPI) biosynthesis, which is the de-N-acetylation of N-acetylglucosaminylphosphatidylinositol (GlcNAc-PI). Study of a similar rat enzyme suggests that this protein localizes to the endoplasmic reticulum. [provided by RefSeq, Jul 2008]

PIGL links:

PIGL (HGNC:):

PIGL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 229) in uniprot entity PIGL_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_004278.4

BP4

Computational evidence support a benign effect (MetaRNN=0.015003979).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000866 (132/152344) while in subpopulation SAS AF= 0.00186 (9/4830). AF 95% confidence interval is 0.00107. There are 0 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGL	NM_004278.4 linkuse as main transcript	c.337G>T	p.Asp113Tyr	missense_variant, splice_region_variant	3/7	ENST00000225609.10	NP_004269.1	Q9Y2B2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGL	ENST00000225609.10 linkuse as main transcript	c.337G>T	p.Asp113Tyr	missense_variant, splice_region_variant	3/7	1	NM_004278.4	ENSP00000225609.5		Q9Y2B2-1

Frequencies

GnomAD3 genomes

AF:

0.000874

AC:

133

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000962

AC:

242

AN:

251446

Hom.:

AF XY:

0.00103

AC XY:

140

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00212

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00127

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.00108

AC:

1570

AN:

1459644

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

817

AN XY:

726300

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.000402

Gnomad4 ASJ exome

AF:

0.000804

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00225

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00113

Gnomad4 OTH exome

AF:

0.000995

GnomAD4 genome

AF:

0.000866

AC:

132

AN:

152344

Hom.:

Cov.:

AF XY:

0.000832

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00129

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000835

Hom.:

Bravo

AF:

0.000714

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000947

AC:

115

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00120

EpiControl

AF:

0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

CHIME syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

PIGL-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2022

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

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.74

D;D;D;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.68

T;T;T;T

M_CAP

Benign

0.061

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Pathogenic

3.2

.;.;M;.

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.4

.;.;D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0090

.;.;D;D

Sift4G

Uncertain

0.0050

D;D;D;D

Polyphen

0.029

.;.;B;.

Vest4

0.23

MVP

0.86

MPC

0.16

ClinPred

0.073

GERP RS

-0.13

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.52

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.0040

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