Variant: NM_000212.2(ITGB3):c.1299C>T (p.Pro433=)

CA8623241

323866 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 77c51cf2-073d-4123-9bca-809de4125661

Approved on: 2023-12-19

Published on: 2023-12-19

HGVS expressions

NM_000212.2:c.1299C>T
NM_000212.2(ITGB3):c.1299C>T (p.Pro433=)
NC_000017.11:g.47292177C>T
CM000679.2:g.47292177C>T
NC_000017.10:g.45369543C>T
CM000679.1:g.45369543C>T
NC_000017.9:g.42724542C>T
NG_008332.2:g.43336C>T
ENST00000559488.7:c.1299C>T
ENST00000559488.5:c.1299C>T
ENST00000560629.1:c.1264C>T
NM_000212.3:c.1299C>T
NM_000212.3(ITGB3):c.1299C>T (p.Pro433=)

Likely Benign

• Met criteria codes: BS1 BP7 BP4

• Not Met criteria codes: BS2

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_000212.2(ITGB3):c.1299C>T (p.Pro433=) synonymous variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population and has been reported in the literature in a healthy cohort (PMID: 27965976) but has not been reported in a Glanzmann thrombasthenia patient. In gnomAD v4.0.0 the minor allele frequency is 0.001910 (174/91086 alleles) in the South Asian population, which meets the BS1 threshold (>0.00158). Splicing prediction algorithms (MaxEntScan, HSF, and SpliceAI) predict no impact on splicing (BP4) and the nucleotide is not highly conserved (phyloP score 0.129449; BP7). In summary this variant meets criteria to be classified as likely benign. GT-specific criteria applied: BS1, BP4 and BP7.

Met criteria codes

• BS1: The highest population minor allele frequency in gnomAD v4.0.0 is 0.002969 (18/6062 alleles) in the Middle Eastern population, which is higher than the ClinGen PD VCEP BA1 threshold (>0.0024), due to this being a bottle-necked population this was downgraded to BS1. The next highest minor allele frequency in gnomAD v4.0.0 is 0.001910 (174/91086 alleles) in the South Asian population, which also meets the BS1 threshold (>0.00158).
• BP7: Splicing prediction algorithms (MaxEntScan, HSF, and SpliceAI) predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved (phyloP score 0.129449).
• BP4: Splicing prediction algorithms (MaxEntScan, HSF, and SpliceAI) predict no impact to the splice consensus sequence nor the creation of a new splice site. CADD RawScore 0.645923 and PHRED 10.70.

Not Met criteria codes

• BS2: One healthy native Chinese subject, in PMID: 27965976, was identified with this variant however the full genotype and phenotype was not provided for this individual.