Variant: NM_000419.5:c.1947-9T>C

CA2825000789

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 0b37294e-3193-4008-b0cc-18f8924631ae

Approved on: 2024-08-20

Published on: 2024-08-20

HGVS expressions

NM_000419.5:c.1947-9T>C
NC_000017.11:g.44378518A>G
CM000679.2:g.44378518A>G
NC_000017.10:g.42455886A>G
CM000679.1:g.42455886A>G
NC_000017.9:g.39811412A>G
NG_008331.1:g.15988T>C
ENST00000262407.6:c.1947-9T>C
ENST00000648408.1:c.1378-9T>C
ENST00000262407.5:c.1947-9T>C
ENST00000592462.5:n.742-9T>C
NM_000419.3:c.1947-9T>C
NM_000419.4:c.1947-9T>C

Uncertain Significance

• Met criteria codes: PP4_Moderate PM2_Supporting BP7

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000419.5(ITGA2B):c.1947-9T>C variant is an intronic variant that is not predicted by SpliceAI to impact splicing (delta scores <0.05). In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of -0.425 (BP7). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband (https://doi.org/10.1182/blood-2023-182694) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was absent or reduced, as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries. In summary, this variant is of uncertain significance. GT-specific criteria applied: BP7, PP4_Moderate, PM2_supporting.

Met criteria codes

• PP4_Moderate: At least one proband (https://doi.org/10.1182/blood-2023-182694) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was absent or reduced, as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries.
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
• BP7: The NM_000419.5(ITGA2B):c.1947-9T>C variant is an intronic variant that is not predicted by SpliceAI to impact splicing (delta scores <0.05). In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of -0.425 (BP7).