rs267606849
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_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
NM_000173.7 stop_gained
Scores
2
3
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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 genomes
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32
GnomAD3 exomes AF: 0.0000281 AC: 7AN: 248922Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135068
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GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461346Hom.: 0 Cov.: 37 AF XY: 0.0000151 AC XY: 11AN XY: 726916
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
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
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at