17-44372364-T-TCACTC
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong
The NM_000419.5(ITGA2B):c.3119_3120insGAGTG(p.Ter1040TrpfsTer?) variant causes a frameshift, stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Genomes: not found (cov: 31)
Consequence
ITGA2B
NM_000419.5 frameshift, stop_lost
NM_000419.5 frameshift, stop_lost
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.808
Genes affected
ITGA2B (HGNC:6138): (integrin subunit alpha 2b) This gene encodes a member of the integrin alpha chain family of proteins. The encoded preproprotein is proteolytically processed to generate light and heavy chains that associate through disulfide linkages to form a subunit of the alpha-IIb/beta-3 integrin cell adhesion receptor. This receptor plays a crucial role in the blood coagulation system, by mediating platelet aggregation. Mutations in this gene are associated with platelet-type bleeding disorders, which are characterized by a failure of platelet aggregation, including Glanzmann thrombasthenia. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 1067 codons.
PP5
?
Variant 17-44372364-T-TCACTC is Pathogenic according to our data. Variant chr17-44372364-T-TCACTC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 952996.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITGA2B | NM_000419.5 | c.3119_3120insGAGTG | p.Ter1040TrpfsTer? | frameshift_variant, stop_lost | 30/30 | ENST00000262407.6 | |
ITGA2B | XM_011524749.2 | c.3170_3171insGAGTG | p.Ter1057TrpfsTer? | frameshift_variant, stop_lost | 29/29 | ||
ITGA2B | XM_011524750.2 | c.3155_3156insGAGTG | p.Ter1052TrpfsTer? | frameshift_variant, stop_lost | 29/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITGA2B | ENST00000262407.6 | c.3119_3120insGAGTG | p.Ter1040TrpfsTer? | frameshift_variant, stop_lost | 30/30 | 1 | NM_000419.5 | P1 | |
ITGA2B | ENST00000587295.5 | c.312_313insGAGTG | p.Ter105TrpfsTer? | frameshift_variant, stop_lost | 3/3 | 3 | |||
ITGA2B | ENST00000648408.1 | c.2433_2434insGAGTG | p.Ter812TrpfsTer? | frameshift_variant, stop_lost | 25/25 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Glanzmann thrombasthenia Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen | Aug 15, 2023 | The stop loss NM_000419.5(ITGA2B):c.3115_3119dup variant causes Ter1040Trp and extension of the protein by 92 amino acids (PM4). It has been observed in the homozygous state in one patient with a phenotype highly specific to GT, including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and <5% surface expression of αIIbβ3 measured by flow cytometry (PMID: 19691478; PP4_moderate, PM3_supporting). This variant is absent from gnomADv2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM4, PP4_moderate, PM3_supporting (PD VCEP specifications version 2.1). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at