Variant: NM_000419.5(ITGA2B):c.1439+8C>T

CA8603095

323556 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: ead95400-b086-4056-9b56-0f80a148246e

Approved on: 2024-11-07

Published on: 2024-11-07

HGVS expressions

NM_000419.5:c.1439+8C>T
NM_000419.5(ITGA2B):c.1439+8C>T
NC_000017.11:g.44380592G>A
CM000679.2:g.44380592G>A
NC_000017.10:g.42457960G>A
CM000679.1:g.42457960G>A
NC_000017.9:g.39813486G>A
NG_008331.1:g.13914C>T
ENST00000262407.6:c.1439+8C>T
ENST00000648408.1:c.870+8C>T
ENST00000262407.5:c.1439+8C>T
ENST00000592226.5:n.912+8C>T
ENST00000592462.5:n.234+8C>T
NM_000419.3:c.1439+8C>T
NM_000419.4:c.1439+8C>T

Uncertain Significance

• Not Met criteria codes: BP2 BP7 PS2 PS3 BA1 PP4 PP1 PP3 PM6 PM2 PM3 BS2 BS4 BS3 BS1

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 c.1439+8C>T variant in ITGA2B is an intronic variant located in intron 14 of 28. The highest population minor allele frequency in gnomAD v4.1.0 is 0.002770(82/29608 alleles) in the Ashkenazi Jewish population, which is higher than the threshold (<0.0001) for PM2_Supporting. The highest continental population minor allele frequency in gnomAD v4.1.0 is 0.000009322 (11/1180044 alleles) in the European (non-Finnish) population, which is below the BS1 threshold of >0.00158. This intronic variant is not predicted by SpliceAI to impact splicing with a score of 0.01. However, BP7 was not applied because the nucleotide is highly conserved, as shown by phyloP score of 1.9773. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the lack of ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP.

Not Met criteria codes

• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: The c.1439+8C>T is an intronic variant that is not predicted by SpliceAI to impact splicing with a score of 0.01. However, BP7 was not applied because the nucleotide is highly conserved, as shown by phyloP score of 1.9773.
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: The highest population minor allele frequency in gnomAD v4.1.0 is 0.002770 (82/29608 alleles) in the Ashkenazi Jewish population. It would meet the BA1 (>0.0024) threshold, however bottle-necked populations are not considered for BS1 or BA1. The next highest population minor allele frequency in gnomAD v4.1.0 is 0.000009322 (11/1180044 alleles) in the European (non-Finnish) population.
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: The computational predictor REVEL has no data. And the computational splicing predictor SpliceAI indicated that the variant has no predicted impact on splicing with a score of 0.01.
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: The highest population minor allele frequency in gnomAD v4.1.0 is 0.002770 (82/29608 alleles) in the Ashkenazi Jewish population. This is higher than the threshold (<0.0001) for PM2_Supporting.
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline