Variant: NM_000212.3:c.166-14C>A

CA8622881

1330326 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 21f99660-8570-49a7-90aa-7287d412e9b8

Approved on: 2024-08-20

Published on: 2024-08-20

HGVS expressions

NM_000212.3:c.166-14C>A
NC_000017.11:g.47283340C>A
CM000679.2:g.47283340C>A
NC_000017.10:g.45360706C>A
CM000679.1:g.45360706C>A
NC_000017.9:g.42715705C>A
NG_008332.2:g.34499C>A
ENST00000696963.1:c.166-14C>A
ENST00000559488.7:c.166-14C>A
ENST00000559488.5:c.166-14C>A
ENST00000560629.1:c.131-14C>A
ENST00000571680.1:c.166-14C>A
NM_000212.2:c.166-14C>A

Uncertain Significance

• Met criteria codes: PM3_Supporting BP7 PP4_Moderate PM2_Supporting

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 ITGB3 intronic variant NM_000212.3:c.166-14C>A is not predicted by in silico tools to have an impact on splicing and is not highly conserved (BP7). This variant has been observed in homozygosity (PM3_supporting) in one individual with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT03, PMID: 16463284). All requirements for PP4_Moderate are met (GT03 in PMID: 16463284): history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin. This variant is rare in population databases (1/91018 alleles in the South Asian population in gnomAD v4.1.0; PM2_Supporting). In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PP4_Moderate, PM2_Supporting, PM3_Supporting, and BP7.

Met criteria codes

• PM3_Supporting: This variant was reported in homozygosity in one individual (GT03 in PMID: 16463284), sufficient to apply PM3_Supporting.
• BP7: The intronic variant is not predicted to impact the splice consensus sequence according to varSEAK, MaxEntScan, and SpliceAI. The nucleotide is not highly conserved (phyloP score -0.57).
• PP4_Moderate: All requirements for PP4_Moderate are met (GT03 in PMID: 16463284): history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin.
• PM2_Supporting: This variant is rare in population databases. It was observed in 1/91018 alleles in the South Asian population in gnomAD v4.1.0. The frequency of this variant is below the 1/10000 allele threshold required to apply PM2_Supporting.