15-55340602-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_004855.5(PIGB):c.847-10A>G variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.140

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius 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. Variant chr15-55340602-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGB	NM_004855.5	c.847-10A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000164305.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGB	ENST00000164305.10	c.847-10A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004855.5	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32

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: 15 AN: 230292 Hom.: 0 AF XY: 0.0000883 AC XY: 11 AN XY: 124514

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: 64 AN: 1439922 Hom.: 0 Cov.: 28 AF XY: 0.0000531 AC XY: 38 AN XY: 715692

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: 1 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74308

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

Submissions by phenotype

Developmental and epileptic encephalopathy, 80 Pathogenic:4

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). -
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	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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	24
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

Other links and lift over

dbSNP: rs779296101; hg19: chr15-55632800;