15-55340602-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_004855.5(PIGB):c.847-10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000408 in 1,592,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

PIGB
NM_004855.5 intron

Scores

Splicing: ADA: 0.9998

Clinical Significance

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

Conservation

PhyloP100: 0.140

Publications

2 publications found

Variant links:

Genes affected

PIGB (HGNC:8959): (phosphatidylinositol glycan anchor biosynthesis class B) This gene encodes a transmembrane protein that is located in the endoplasmic reticulum and is involved in GPI-anchor biosynthesis. The glycosylphosphatidylinositol (GPI) anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This gene is thought to encode a member of a family of dolichol-phosphate-mannose (Dol-P-Man) dependent mannosyltransferases. [provided by RefSeq, Jul 2008]

PIGB links:

CCPG1 (HGNC:24227): (cell cycle progression 1) Involved in positive regulation of cell cycle and positive regulation of cell population proliferation. Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

CCPG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 15-55340602-A-G is Pathogenic according to our data. Variant chr15-55340602-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 689519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGB	NM_004855.5 link	c.847-10A>G		intron_variant	Intron 7 of 11	ENST00000164305.10	NP_004846.4	Q92521

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGB	ENST00000164305.10 link	c.847-10A>G		intron_variant	Intron 7 of 11	1	NM_004855.5	ENSP00000164305.5		Q92521

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000651

AC:

AN:

230292

AF XY:

0.0000883

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:

0.0000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000444

AC:

AN:

1439922

Hom.:

Cov.:

AF XY:

0.0000531

AC XY:

AN XY:

715692

show subpopulations

African (AFR)

AF:

0.0000605

AC:

AN:

33048

American (AMR)

AF:

0.00

AC:

AN:

42576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25738

East Asian (EAS)

AF:

0.00

AC:

AN:

39372

South Asian (SAS)

AF:

0.000524

AC:

AN:

83908

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52828

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.0000155

AC:

AN:

1097194

Other (OTH)

AF:

0.0000168

AC:

AN:

59644

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 80

Pathogenic:4

Jul 27, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 20, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 23, 2023

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This homozygous intronic variant is identified in a 3 month male with poor feeding, coarse face, who later developed GDD hypertrichosis and raised alkaline phosphatase. Microanalysis: normal. Sibling died with a similar phenotype. This change present in gnomAD database with an allele frequency of 0.0065% [PM2]. To our knowledge there are no homozygotes in gnomAd database for this variant. Insilico prediction [SpliceAI, dbscSNV] predicts a splice-altering nature of this variant [PP3]. A clinvar entry [Variation ID: 689519] for this variant is available with a “Pathogenic” interpretation by multiple submitter. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic" -

Nov 03, 2021

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PIGB c.847-10A>G variant is classified as PATHOGENIC (PS4, PVS1) The PIGB c.847-10A>G is a single nucleotide change located in intron 7 of the gene. Studies have demonstrated that this variant introduces a new acceptor site and results in no wild-type mRNA being expressed (PMID:31256876). This variant has been previously reported in a homozygous state in affected individuals from multiple families with glycosylphosphatidylinositol deficiency (PMID:31256876) (PS4). This variant is in dbSNP (rs779296101) but is rare in population databases (gnomAD 1/152128 alleles). This variant has been reported in ClinVar as pathogenic for developmental and epileptic encephalopathy 80 by another diagnostic laboratory (Variation ID:689519). It is also reported as damaging in the disease database HGMD (CS1915182). -

not provided

Pathogenic:1

Jan 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 7 of the PIGB gene. It does not directly change the encoded amino acid sequence of the PIGB protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 3 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs779296101, gnomAD 0.05%). This variant has been observed in individual(s) with PIGB-related conditions (PMID: 31256876). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 689519). Studies have shown that this variant alters PIGB gene expression (PMID: 31256876, 32123317). Studies have shown that this variant results in the activation of a cryptic splice site in intron 7 (PMID: 31256876). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Uncertain

(source)

DANN

Benign

0.79

PhyloP100

0.14

Mutation Taster

=45/55

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

Splicevardb

3.0

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.98

Position offset: 1

DS_AL_spliceai

0.80

Position offset: 10

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

Publications

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15-55340602-A-G

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