17-16299976-C-A

Position:

chr17-16299976-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004278.4(PIGL):c.424C>A(p.Leu142Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00584 in 1,611,252 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 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 0.0048 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0060 ( 41 hom. )

Consequence

PIGL
NM_004278.4 missense, splice_region

Scores

Splicing: ADA: 0.0009913

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 0.182

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008395642).

BP6

Variant 17-16299976-C-A is Benign according to our data. Variant chr17-16299976-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159705.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00481 (732/152282) while in subpopulation NFE AF= 0.00745 (507/68016). AF 95% confidence interval is 0.00692. There are 6 homozygotes in gnomad4. There are 333 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGL	NM_004278.4 linkuse as main transcript	c.424C>A	p.Leu142Met	missense_variant, splice_region_variant	3/7	ENST00000225609.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGL	ENST00000225609.10 linkuse as main transcript	c.424C>A	p.Leu142Met	missense_variant, splice_region_variant	3/7	1	NM_004278.4	P1	Q9Y2B2-1

Frequencies

GnomAD3 genomes

AF:

0.00481

AC:

732

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00675

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00745

Gnomad OTH

AF:

0.00622

GnomAD3 exomes

AF:

0.00509

AC:

1280

AN:

251468

Hom.:

AF XY:

0.00520

AC XY:

707

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00535

Gnomad ASJ exome

AF:

0.00804

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.00768

Gnomad OTH exome

AF:

0.00798

GnomAD4 exome

AF:

0.00595

AC:

8681

AN:

1458970

Hom.:

Cov.:

AF XY:

0.00586

AC XY:

4255

AN XY:

726104

show subpopulations

Gnomad4 AFR exome

AF:

0.000987

Gnomad4 AMR exome

AF:

0.00575

Gnomad4 ASJ exome

AF:

0.00888

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00133

Gnomad4 FIN exome

AF:

0.00182

Gnomad4 NFE exome

AF:

0.00683

Gnomad4 OTH exome

AF:

0.00558

GnomAD4 genome

AF:

0.00481

AC:

732

AN:

152282

Hom.:

Cov.:

AF XY:

0.00447

AC XY:

333

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.00674

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00188

Gnomad4 NFE

AF:

0.00745

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00717

Hom.:

Bravo

AF:

0.00518

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00709

AC:

ExAC

AF:

0.00498

AC:

604

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00774

EpiControl

AF:

0.00895

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 06, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PIGL: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

CHIME syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Coloboma, Congenital Heart Disease, Ichthyosiform Dermatosis, Intellectual Disability, and Ear Anomalies (CHIME) Syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 22, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.015

T;T;T;.

Eigen

Benign

0.020

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.21

T;T;T;T

M_CAP

Benign

0.043

MetaRNN

Benign

0.0072

T;T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Uncertain

2.0

.;.;M;.

MutationTaster

Benign

0.83

D;D;D;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.75

.;.;N;N

REVEL

Uncertain

0.48

Sift

Benign

0.089

.;.;T;T

Sift4G

Pathogenic

0.0

D;T;T;T

Polyphen

0.98

.;.;D;.

Vest4

0.39

MVP

0.82

MPC

0.44

ClinPred

0.020

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00099

dbscSNV1_RF

Benign

0.014

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