NM_004278.4:c.500T>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3PP5_Very_Strong

The NM_004278.4(PIGL):c.500T>C(p.Leu167Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000739 in 1,605,302 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000915744: Cell lines derived from a patient who was compound heterozygous for the p.Leu167Pro variant and a chromosome 17 deletion were deficient in two glycosylphosphatidylinositol markers, demonstrating a detrimental functional effect of the variant." and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 0 hom. )

Consequence

PIGL
NM_004278.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:24U:2O:1

Conservation

PhyloP100: 4.74

Publications

14 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: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
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: Pathogenic. The variant received 12 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000915744: Cell lines derived from a patient who was compound heterozygous for the p.Leu167Pro variant and a chromosome 17 deletion were deficient in two glycosylphosphatidylinositol markers, demonstrating a detrimental functional effect of the variant.; SCV000400868: Cell lines derived from a patient who was compound heterozygous for the p.Leu167Pro variant and a chromosome 17 deletion were deficient in two glycosylphosphatidylinositol markers, demonstrating a detrimental functional effect of the variant.

PP5

Variant 17-16316686-T-C is Pathogenic according to our data. Variant chr17-16316686-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 30544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004278.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGL	NM_004278.4	MANE Select	c.500T>C	p.Leu167Pro	missense	Exon 5 of 7	NP_004269.1	Q9Y2B2-1
	PIGL	NM_001411072.1		c.495-1089T>C		intron	N/A	NP_001398001.1	A8MTV0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIGL	ENST00000225609.10	TSL:1 MANE Select	c.500T>C	p.Leu167Pro	missense	Exon 5 of 7	ENSP00000225609.5	Q9Y2B2-1
PIGL	ENST00000584797.5	TSL:3	c.500T>C	p.Leu167Pro	missense	Exon 5 of 6	ENSP00000463540.1	J3QLG8
PIGL	ENST00000395844.8	TSL:5	c.495-1089T>C		intron	N/A	ENSP00000379185.3	A8MTV0

Frequencies

GnomAD3 genomes

AF:

0.000604

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000414

AC:

104

AN:

251422

AF XY:

0.000383

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.000651

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000754

AC:

1095

AN:

1452948

Hom.:

Cov.:

AF XY:

0.000728

AC XY:

525

AN XY:

721112

show subpopulations

African (AFR)

AF:

0.0000899

AC:

AN:

33362

American (AMR)

AF:

0.000179

AC:

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26016

East Asian (EAS)

AF:

0.00

AC:

AN:

39436

South Asian (SAS)

AF:

0.000140

AC:

AN:

85814

European-Finnish (FIN)

AF:

0.000844

AC:

AN:

53296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.000910

AC:

1005

AN:

1104746

Other (OTH)

AF:

0.000367

AC:

AN:

59942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

105

158

210

263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

138

184

230

<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:

0.000597

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41586

American (AMR)

AF:

0.00105

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000847

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000838

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000692

Hom.:

Bravo

AF:

0.000495

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000329

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

CHIME syndrome (13)

not provided (10)

Hypertelorism;C0151526:Premature birth;C0239234:Low-set ears;C0409348:Camptodactyly of finger;C0431659:Hypoplasia of scrotum;C0431904:Postaxial hand polydactyly;C1398522:Bilateral cleft lip and palate;C1827524:Wide intermamillary distance (1)

Inborn genetic diseases (1)

Intellectual disability (1)

PIGL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.66

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.55

MetaSVM

Uncertain

0.40

MutationAssessor

Pathogenic

3.0

PhyloP100

4.7

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.6

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.96

MVP

0.94

MPC

0.70

ClinPred

0.19

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

0.92

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over