17-44372390-C-CCA
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4
The NM_000419.5(ITGA2B):c.3093_3094insTG(p.Glu1032TrpfsTer?) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000294 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
ITGA2B
NM_000419.5 frameshift
NM_000419.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.405
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 Uncertain_significance. Variant got 2 ACMG points.
PM4
?
Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 1035 codons.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITGA2B | NM_000419.5 | c.3093_3094insTG | p.Glu1032TrpfsTer? | frameshift_variant | 30/30 | ENST00000262407.6 | |
ITGA2B | XM_011524749.2 | c.3144_3145insTG | p.Glu1049TrpfsTer? | frameshift_variant | 29/29 | ||
ITGA2B | XM_011524750.2 | c.3129_3130insTG | p.Glu1044TrpfsTer? | frameshift_variant | 29/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITGA2B | ENST00000262407.6 | c.3093_3094insTG | p.Glu1032TrpfsTer? | frameshift_variant | 30/30 | 1 | NM_000419.5 | P1 | |
ITGA2B | ENST00000587295.5 | c.286_287insTG | p.Glu97TrpfsTer? | frameshift_variant | 3/3 | 3 | |||
ITGA2B | ENST00000648408.1 | c.2407_2408insTG | p.Glu804TrpfsTer? | frameshift_variant | 25/25 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461880Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16AN XY: 727242
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GnomAD4 genome ? Cov.: 31
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Glanzmann thrombasthenia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the C-terminus of the ITGA2B protein. Other variant(s) that disrupt this region (p.*1040Trpext*) have been observed in individuals with ITGA2B-related conditions (PMID: 19691478). This suggests that this may be a clinically significant region of the protein. ClinVar contains an entry for this variant (Variation ID: 953020). This variant is also known as 3094insTG. This frameshift has been observed in individual(s) with Glanzmann Thrombasthenia (PMID: 9215749). This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the ITGA2B gene (p.Glu1032Trpfs*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acids of the ITGA2B protein and extend the protein. - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen | Jun 01, 2023 | The NM_000419.5(ITGA2B):c.3092_3093dup variant results in a frameshift, p.Glu1032TrpfsTer98, and introduction of a stop codon further than the original. This adds 90 amino acids to the ITGA2B protein. The variant is absent from population databases, including gnomADv2.1.1 (PM2_supporting). It is reported in a compound heterozygous individual with the c.3060+2T>C variant (classified Pathogenic by the PD VCEP; PM3_supporting); however, the individual does not meet criteria for PP4 (PMID: 9215749). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, BP4 (PD VCEP specifications version 2.1). - |
Platelet-type bleeding disorder 16 Pathogenic:1
Pathogenic, no assertion criteria provided | research | ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | - | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at