Variant: NM_000212.3(ITGB3):c.1800G>A (p.Leu600=)

CA8623360

695455 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 38ea2b05-0e7a-4c13-9d7b-d6a15daf38ff

Approved on: 2024-04-16

Published on: 2024-04-16

HGVS expressions

NM_000212.3:c.1800G>A
NM_000212.3(ITGB3):c.1800G>A (p.Leu600=)
NC_000017.11:g.47299417G>A
CM000679.2:g.47299417G>A
NC_000017.10:g.45376783G>A
CM000679.1:g.45376783G>A
NC_000017.9:g.42731782G>A
NG_008332.2:g.50576G>A
ENST00000696963.1:c.1800G>A
ENST00000559488.7:c.1800G>A
ENST00000559488.5:c.1800G>A
ENST00000560629.1:c.1765G>A
NM_000212.2:c.1800G>A

Uncertain Significance

• Met criteria codes: BS1

• Not Met criteria codes: BS2 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_000212.3(ITGB3):c.1800G>A (p.Leu600=) synonymous variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population but has not been reported in a GT patient. The variant occurs at an allele frequency greater than expected for the disorder with a MAF of 0.01233 (365/29608 alleles, with 5 homozygotes) in the gnomADv4.0.0 Ashkenazi Jewish population (BS1). It is not predicted to have an impact on splicing consensus sites but the nucleotide is highly conserved. In summary there is insufficient evidence resulting in a classification of Uncertain Significance. GT-specific criteria applied: BS1.

Met criteria codes

• BS1: The overall allele frequency in gnomADv4.0.0 is 0.0003277 with a MAF of 0.01233 (365/29608 alleles, with 5 homozygotes) in the Ashkenazi Jewish population. This is above the BA1 threshold of >0.0024, however because this is a bottle-necked population the more conservative BS1 criterion was applied. The next highest MAF is 0.0003299 (2/6062 alleles) in the Middle Eastern population which is an intermediate allele frequency, below the BS1 threshold of >0.00158 but above the PM2 threshold of <0.0001.

Not Met criteria codes

• BS2: Although homozygosity (5 individuals in gnomAD Ashkenazi Jewish cohort) has been reported in population databases of reportedly healthy individuals, phenotypic data is not available.
• BP7: Splicing prediction algorithms (MaxEntScan, HSF, and SpliceAI) predict no impact to the splice consensus sequence nor the creation of a new splice site, however HSF does predict significant alteration of ESE / ESS motifs. Additionally, the nucleotide is highly conserved (phyloP score 3.86282).