NM_004278.4:c.427-1G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1PS3PM2PP5_Very_Strong

The NM_004278.4(PIGL):c.427-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,612,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005400584: "A fibroblast cell line from an individual with compound heterozygous variants NM_004278.3:c.427-1G>A and NM_004278.3:c.500T>C showed deficiency in cell surface GPI anchor markers, CD59 and aerolysin (PMID:22444671)."".

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

PIGL
NM_004278.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.42

Publications

2 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 22 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.4, offset of 1, new splice context is: accctgtgtttctctacaAGtgg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PS3

PS3 evidence extracted from ClinVar submissions: SCV005400584: "A fibroblast cell line from an individual with compound heterozygous variants NM_004278.3:c.427-1G>A and NM_004278.3:c.500T>C showed deficiency in cell surface GPI anchor markers, CD59 and aerolysin (PMID: 22444671)."

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-16313546-G-A is Pathogenic according to our data. Variant chr17-16313546-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 30547.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.427-1G>A		splice_acceptor intron	N/A	NP_004269.1	Q9Y2B2-1
	PIGL	NM_001411072.1		c.427-1G>A		splice_acceptor intron	N/A	NP_001398001.1	A8MTV0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PIGL	ENST00000225609.10	TSL:1 MANE Select	c.427-1G>A	splice_acceptor intron	N/A	ENSP00000225609.5	Q9Y2B2-1
PIGL	ENST00000395844.8	TSL:5	c.427-1G>A	splice_acceptor intron	N/A	ENSP00000379185.3	A8MTV0
PIGL	ENST00000584797.5	TSL:3	c.427-1G>A	splice_acceptor intron	N/A	ENSP00000463540.1	J3QLG8

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251488

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1460060

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726508

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000261

AC:

AN:

1110340

Other (OTH)

AF:

0.0000497

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.0000679

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

CHIME syndrome (2)

not provided (2)

Syndromic intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.92

PhyloP100

3.4

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.92

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.92

Position offset: 1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over