17-4932764-CTGAG-C

Position:

• chr17-4932764-CTGAG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP4 PM2_Supporting PVS1_Strong PM3_Supporting PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.165_168del (p.Ser55ArgfsTer12) variant in GP1BA is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (removes the final 598 amino acids) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong). At least one patient (Patient 1 in PMID:11054083) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome (PP4). They also had a history of recurrent epistaxis and spontaneous skin bruises and a low platelet count (84x10^9/l). This variant has been detected in at least 2 probands with Bernard-Soulier syndrome. One of those individuals was compound heterozygous for this variant and the c.1601_1602del (p.Tyr534CysfsTer?) variant in GP1BA, confirmed in trans by parental testing (PMID:11054083). This second variant was classified as Pathogenic by the VCEP. (not included here to avoid circularity). The other proband was homozygous for the c.165_168del (p.Ser55ArgfsTer12) variant (PMID:18791947; PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). From PMID:11054083, flow cytometric analysis was performed for GP Iba on CHO cells transiently transfected with the WT + c.165_168del (p.Ser55ArgfsTer12), which had around 60% WT expression levels above sham. They also tested c.165_168del + c.1601_1602del, which had around 5% WT expression levels above sham. Due to the methods used in this assay (where c.165_168del was not tested independently), the usual threshold of <25% WT levels to apply PS3_supporting is not the appropriate measure. The 60% expression of WT + c.165_168del is considered sufficient, particularly in light of the c.165_168del + c.1601_1602del, which had around 5% WT expression levels (PS3_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM2_Supporting and PM3_Supporting, PS3_Supporting (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA658820730/MONDO:0009276/079

• Frequency: Genomes: not found (cov: 32)
• Consequence: GP1BA NM_000173.7 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.65

Genes affected

GP1BA (HGNC:4439): (glycoprotein Ib platelet subunit alpha) Glycoprotein Ib (GP Ib) is a platelet surface membrane glycoprotein composed of a heterodimer, an alpha chain and a beta chain, that is linked by disulfide bonds. The Gp Ib functions as a receptor for von Willebrand factor (VWF). The complete receptor complex includes noncovalent association of the alpha and beta subunits with platelet glycoprotein IX and platelet glycoprotein V. The binding of the GP Ib-IX-V complex to VWF facilitates initial platelet adhesion to vascular subendothelium after vascular injury, and also initiates signaling events within the platelet that lead to enhanced platelet activation, thrombosis, and hemostasis. This gene encodes the alpha subunit. Mutations in this gene result in Bernard-Soulier syndromes and platelet-type von Willebrand disease. The coding region of this gene is known to contain a polymophic variable number tandem repeat (VNTR) domain that is associated with susceptibility to nonarteritic anterior ischemic optic neuropathy. [provided by RefSeq, Oct 2013]

CHRNE (HGNC:1966): (cholinergic receptor nicotinic epsilon subunit) Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GP1BA	NM_000173.7	c.165_168delTGAG	p.Ser55fs	frameshift_variant	2/2	ENST00000329125.6	NP_000164.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GP1BA	ENST00000329125.6	c.165_168delTGAG	p.Ser55fs	frameshift_variant	2/2	1	NM_000173.7	ENSP00000329380.5
CHRNE	ENST00000649830.1	c.-888+1574_-888+1577delCTCA		intron_variant				ENSP00000496907.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 03, 2023

Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This sequence change creates a premature translational stop signal (p.Ser55Argfs*12) in the GP1BA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 598 amino acid(s) of the GP1BA protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Bernard-Soulier syndrome (PMID: 11054083, 18791947). This variant is also known as p.Ser39fs. Experimental studies have shown that this premature translational stop signal affects GP1BA function (PMID: 11054083). This variant disrupts a region of the GP1BA protein in which other variant(s) (p.Trp540*) have been determined to be pathogenic (PMID: 9233564, 9639514). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-4836059;