Variant: NM_001754.5(RUNX1):c.-60+38dup

CA637749766

1268886 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: e045b5a6-1aa6-4f0d-b25e-9f817a8381dc

Approved on: 2024-06-24

Published on: 2024-06-24

HGVS expressions

NM_001754.5:c.-60+38dup
NM_001754.5(RUNX1):c.-60+38dup
NC_000021.9:g.35049130dup
CM000683.2:g.35049130dup
NC_000021.8:g.36421427dup
CM000683.1:g.36421427dup
NC_000021.7:g.35343297dup
NG_011402.2:g.940596dup
ENST00000675419.1:c.-60+52dup
ENST00000300305.7:c.-217dup
ENST00000416754.1:c.-95dup
ENST00000437180.5:c.-60+52dup
ENST00000455571.5:c.-60+52dup
ENST00000475045.6:c.-59-158dup
ENST00000482318.5:c.-60+52dup
NM_001754.4:c.-60+52dup
NM_001754.5:c.-60+52dup

Benign

• Met criteria codes: BP7 BP4 BP2 BA1

• Not Met criteria codes: BS4 BS3 BS1 BS2 BP1 BP3 PVS1 PS4 PS2 PS1 PS3 PP1 PP3 PP2 PP4 PM6 PM2 PM5 PM1 PM4 PM3

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

Evidence submitted by expert panel

Myeloid Malignancy VCEP

The NM_001754.5(RUNX1):c.-60+52dup variant is a deep intronic variant in a homopolymer region that is not predicted by SpliceAI to impact splicing (BP4). The variant highest minor allele frequency (MAF) is 0.05560 (5.0%, 396/7122 alleles) in the African/African American subpopulation of the gnomAD2.1.1 ( ≥ 0.0015 (0.15%) (BP1)). Additionally, this variant is detected in a homozygous state in 10 individuals in a population database (gnomADv2.1.1) (BP2). This deep intronic variant is not well conserved with a phyloP100way score of 0.9 (BP7 ≤2.0). It has not been reported in individuals meeting at least one of the RUNX1 phenotypic criteria. In summary, the clinical significance of this variant is Benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP1, BP2, BP4, BP7

Met criteria codes

• BP7: This deep intronc variant is not well conserved with a phyloP100way score of 0.9 (≤2.0)
• BP4: SpliceAI score of 0.03 (≤ 0.20)
• BP2: This variant is detected in a homozygous state in 10 individuals in a population database (gnomADv2.1.1)
• BA1: MAF of 0.05560 (5.0%, 396/7122 alleles) in the African/African American subpopulation of the gnomAD2.1.1 cohort is ≥ 0.0015 (0.15%)

Not Met criteria codes

• BS4: No case study found
• BS3: No studies found
• BS1: BA1 Met
• BS2: This rule is not applicable for MM-VCEP
• BP1: This rule is not applicable for MM-VCEP
• BP3: This rule is not applicable for MM-VCEP
• PVS1: Not predicted to be a null variant
• PS4: No case study found
• PS2: No case study found
• PS1: No amino acid change predicted
• PS3: No studies found
• PP1: No case study found
• PP3: Not a missense variant
• PP2: This rule is not applicable for MM-VCEP
• PP4: This rule is not applicable for MM-VCEP
• PM6: No case study found
• PM2: BA1 Met
• PM5: Not a missense variant
• PM1: Not in a hotspot or well established functional domain
• PM4: No change in protein length predicted
• PM3: This rule is not applicable for MM-VCEP