15-55319323-C-T

Variant names:

• chr15-55319323-C-T
• NM_004855.5:c.73C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004855.5(PIGB):​c.73C>T​(p.Gln25*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PIGB NM_004855.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.95
• Publications: 0 publications found

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]

PIGBOS1 (HGNC:50696): (PIGB opposite strand 1) Involved in regulation of endoplasmic reticulum unfolded protein response. Is integral component of mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

RAB27A (HGNC:9766): (RAB27A, member RAS oncogene family) The protein encoded by this gene belongs to the small GTPase superfamily, Rab family. The protein is membrane-bound and may be involved in protein transport and small GTPase mediated signal transduction. Mutations in this gene are associated with Griscelli syndrome type 2. Alternative splicing occurs at this locus and four transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

RAB27A Gene-Disease associations (from GenCC):

• Griscelli syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 25 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-55319323-C-T is Pathogenic according to our data. Variant chr15-55319323-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2098872.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGB	NM_004855.5	c.73C>T	p.Gln25*	stop_gained	Exon 1 of 12	ENST00000164305.10	NP_004846.4
PIGBOS1	NM_001308421.2	c.-535G>A		upstream_gene_variant		ENST00000436697.3	NP_001295350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGB	ENST00000164305.10	c.73C>T	p.Gln25*	stop_gained	Exon 1 of 12	1	NM_004855.5	ENSP00000164305.5
PIGB	ENST00000566999.5	c.73C>T	p.Gln25*	stop_gained	Exon 1 of 6	3		ENSP00000456531.1
PIGBOS1	ENST00000436697.3	c.-535G>A		upstream_gene_variant		2	NM_001308421.2	ENSP00000484893.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1441920 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 715076

African (AFR) AF: 0.00 AC: 0 AN: 33226

American (AMR) AF: 0.00 AC: 0 AN: 41500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25532

East Asian (EAS) AF: 0.00 AC: 0 AN: 39152

South Asian (SAS) AF: 0.00 AC: 0 AN: 82580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102560

Other (OTH) AF: 0.00 AC: 0 AN: 59644

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Sep 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln25*) in the PIGB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PIGB are known to be pathogenic (PMID: 31256876, 34400385). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of PIGB-related conditions (PMID: 31175295). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.031
FATHMM_MKL	Benign	0.10	N
PhyloP100		1.9
Vest4		0.070
GERP RS		5.0
PromoterAI		0.0052	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr15-55611521;