rs115958467

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 15/24 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

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

CHIME syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet, PanelApp Australia
syndromic intellectual disability
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hyperphosphatasia-intellectual disability syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PIGL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 159705.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGL	NM_004278.4 link	c.424C>A	p.Leu142Met	missense_variant, splice_region_variant	Exon 3 of 7	ENST00000225609.10	NP_004269.1	Q9Y2B2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGL	ENST00000225609.10 link	c.424C>A	p.Leu142Met	missense_variant, splice_region_variant	Exon 3 of 7	1	NM_004278.4	ENSP00000225609.5		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

GnomAD2 exomes

AF:

0.00509

AC:

1280

AN:

251468

AF XY:

0.00520

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 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

African (AFR)

AF:

0.000987

AC:

AN:

33430

American (AMR)

AF:

0.00575

AC:

257

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00888

AC:

232

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00133

AC:

115

AN:

86212

European-Finnish (FIN)

AF:

0.00182

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00526

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00683

AC:

7581

AN:

1109402

Other (OTH)

AF:

0.00558

AC:

336

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

360

721

1081

1442

1802

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

274

548

822

1096

1370

<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:

0.00481

AC:

732

AN:

152282

Hom.:

Cov.:

AF XY:

0.00447

AC XY:

333

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

41566

American (AMR)

AF:

0.00674

AC:

103

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00124

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00745

AC:

507

AN:

68016

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

130

174

217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00671

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

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 06, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PIGL: BP4, BS2 -

CHIME syndrome

Uncertain:1Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Sep 22, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.

PhyloP100

0.18

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

Mutation Taster

=93/7

polymorphism

(source)

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

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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