15-55340602-A-G

Position:

chr15-55340602-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_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

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:

PIGB (HGNC:):

PIGB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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. Variant chr15-55340602-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGB	NM_004855.5 linkuse as main transcript	c.847-10A>G		intron_variant		ENST00000164305.10	NP_004846.4	Q92521

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGB	ENST00000164305.10 linkuse as main transcript	c.847-10A>G		intron_variant		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

GnomAD3 exomes

AF:

0.0000651

AC:

AN:

230292

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

124514

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 SAS exome

AF:

0.000459

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

Gnomad4 AFR exome

AF:

0.0000605

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000524

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000155

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Oct 23, 2023	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" -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 03, 2021	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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 07, 2024

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

DANN

Benign

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

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

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