Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000174.5(GP9):c.459G>A (p.Ala153=)

CA2602720

1122031 (ClinVar)

Gene: GP9
Condition: Bernard-Soulier syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: b8f41955-a83d-49c1-884c-333ab1bd32fa
Approved on: 2025-02-11
Published on: 2025-02-14

HGVS expressions

NM_000174.5:c.459G>A
NM_000174.5(GP9):c.459G>A (p.Ala153=)
NC_000003.12:g.129062198G>A
CM000665.2:g.129062198G>A
NC_000003.11:g.128781041G>A
CM000665.1:g.128781041G>A
NC_000003.10:g.130263731G>A
NG_008715.1:g.6397G>A
ENST00000307395.5:c.459G>A
ENST00000307395.4:c.459G>A
NM_000174.4:c.459G>A
More

Likely Benign

Met criteria codes 2
BP7 BP4
Not Met criteria codes 3
BS1 PP4 PM2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GP9 Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Platelet Disorders VCEP
The c.459G>A variant is a synonymous (silent) variant (p.Ala153=) that is not predicted by splice AI to impact splicing (BP4) and occurs at a nucleotide that is not highly conserved as shown by phyloP score of -3.75 (BP7). The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.00003753 (based on 7/86580 alleles) in the South Asian population, which is above the ClinGen PD VCEP PM2_supporting threshold (<0.0000329) but below the BS1 threshold (>0.0007). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Bernard-Soulier syndrome based on PD specifications of ACMG/AMP guidelines: BP4, BP7.
Met criteria codes
BP7
The c.459G>A (p.Ala153=) variant is a synonymous that is not predicted by SpliceAI to impact splicing (score <0.2). In addition, it occurs at a nucleotide that is not highly conserved as shown by phyloP score of -3.75 (<1.5) (BP7).
BP4
The computational splicing predictor SpliceAI indicated that the variant has no impact on splicing.
Not Met criteria codes
BS1
The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.00003753 (based on 7/86580 alleles) in the South Asian population, which is above the ClinGen PD VCEP PM2_supporting threshold (<0.0000329) but below the BS1 threshold (>0.0007).
PP4
Report of a patient 27 with genetically confirmed 22q11 deletion syndrome who harbors this GP9 variant. Patient had ISTH-BAT score of 9, 91% GPIb-IX-V expression. Patients with 22q11DS are carriers of Bernard-Soulier syndrome due to the deletion of GP1BB on one allele. Patient had GP1BB variant NM_000407.5(GP1BB):c.*107C>T, which is classified as benign by the PD VCEP. Authors concluded that the ISTH-BAT scores are not determined by GP1BB hemizygosity alone. PP4 not met as GP9 variant is irrelevant to their bleeding symptoms.
PM2
The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.00003753 (based on 7/86580 alleles) in the South Asian population, which is above the ClinGen PD VCEP PM2_supporting threshold (<0.0000329) but below the BS1 threshold (>0.0007).
Curation History
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