rs267606849

chr17-4934224-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000173.7(GP1BA):c.1620G>A(p.Trp540Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,346 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.000014 (0 hom.)
• Consequence: GP1BA NM_000173.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.78

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: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-4934224-G-A is Pathogenic according to our data. Variant chr17-4934224-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4157.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-4934224-G-A is described in Lovd as [Pathogenic]. Variant chr17-4934224-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GP1BA	NM_000173.7	c.1620G>A	p.Trp540Ter	stop_gained	2/2	ENST00000329125.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GP1BA	ENST00000329125.6	c.1620G>A	p.Trp540Ter	stop_gained	2/2	1	NM_000173.7	P1
CHRNE	ENST00000649830.1	c.-888+118C>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000281 AC: 7 AN: 248922 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135068

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000621

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461346 Hom.: 0 Cov.: 37 AF XY: 0.0000151 AC XY: 11 AN XY: 726916

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000331 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Bernard-Soulier syndrome, type A1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1997

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 02, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects GP1BA protein function (PMID: 9639514). This variant has been observed in individual(s) with Bernard-Soulier syndrome (PMID: 9233564, 9639514). It has also been observed to segregate with disease in related individuals. This variant is also known as c.2078G>A (p.W498*). ClinVar contains an entry for this variant (Variation ID: 4157). This variant is present in population databases (rs267606849, ExAC 0.006%). This sequence change creates a premature translational stop signal (p.Trp540*) in the GP1BA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 113 amino acid(s) of the GP1BA protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	39
Dann	Uncertain	0.99
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.65	D
MutationTaster	Benign	1.0	D
Vest4		0.78
GERP RS		4.0

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

LitVar

Other links and lift over

dbSNP: rs267606849; hg19: chr17-4837519;