Variant: NM_000212.3(ITGB3):c.58C>T (p.Leu20=)

CA8622836

323863 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: e677c970-cc94-46af-898a-0bb16dfa91cd

HGVS expressions

NM_000212.3:c.58C>T
NM_000212.3(ITGB3):c.58C>T (p.Leu20=)
NC_000017.11:g.47253919C>T
CM000679.2:g.47253919C>T
NC_000017.10:g.45331285C>T
CM000679.1:g.45331285C>T
NC_000017.9:g.42686284C>T
NG_008332.2:g.5078C>T
ENST00000559488.7:c.58C>T
ENST00000559488.5:c.58C>T
ENST00000560629.1:n.23C>T
ENST00000571680.1:c.58C>T
NM_000212.2:c.58C>T

Benign

• Met criteria codes: BA1 BP4

• Not Met criteria codes: 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

After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.58C>T (p.Leu20=), no individuals with Glanzmann thrombasthenia were reported with the variant. This variant was observed by Ilumina as part of a predisposition screen in an ostensibly healthy population. Moreover, the variant has a minor allele frequency of 0.01438 (146/10154 alleles) in gnomAD, found in the African/African American population, which is considerably higher than the expected frequency of the disease (BA1). In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing. However, BP7 was not applied as the nucleotide position is conserved. In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1 and BP4 (PD VCEP specifications version 2.1).

Met criteria codes

• BA1: The highest population minor allele frequency in gnomAD v2.1.1 is 0.01438 (146/10154 alleles) in the African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.0024), and therefore meets this criterion (BA1).
• BP4: The c.58C>T (p.Leu20=) variant is a synonymous variant that is not predicted by SpliceAI to impact splicing (BP4).

Not Met criteria codes

• BP7: The c.58C>T (p.Leu20=) variant is a synonymous variant that is not predicted by SpliceAI to impact splicing. However, BP7 was not applied because the nucleotide is highly conserved, as shown by phyloP score of 2.816.

Approved on: 2023-03-21

Published on: 2023-03-21