Variant: NM_001754.4(RUNX1):c.508+3delA

CA248618

14466 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: d7a48ae9-bd50-426d-bb9f-589c53013a9b

Approved on: 2024-09-10

Published on: 2024-09-10

HGVS expressions

NM_001754.4:c.508+3delA
NM_001754.4(RUNX1):c.508+3delA
NC_000021.9:g.34880554del
CM000683.2:g.34880554del
NC_000021.8:g.36252851del
CM000683.1:g.36252851del
NC_000021.7:g.35174721del
NG_011402.2:g.1109158del
ENST00000675419.1:c.508+3del
ENST00000300305.7:c.508+3del
ENST00000344691.8:c.427+3del
ENST00000358356.9:c.427+3del
ENST00000399237.6:c.472+3del
ENST00000399240.5:c.427+3del
ENST00000437180.5:c.508+3del
ENST00000482318.5:c.*98+3del
NM_001001890.2:c.427+3del
NM_001122607.1:c.427+3del
NM_001754.4:c.508+3del
NM_001001890.3:c.427+3del
NM_001122607.2:c.427+3del
NM_001754.5:c.508+3del

Pathogenic

• Met criteria codes: PS3 PP1_Strong PS4_Supporting PP3 PM2_Supporting

• Not Met criteria codes: BA1 BS4 BS1 BS3 BS2 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS1 PP4 PP2 PM6 PM3 PM5 PM1 PM4 PVS1

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

There is RT-PCR assay evidence demonstrating that the NM_001754.4:c.508+3delA variant creates a cryptic splice donor site that is used and results in a frameshift and introduction of premature termination codon (PS3; PMID: 11830488). This variant was found to co-segregate with disease in multiple affected family members, with eight meioses observed in one family (PP1_Strong; PMID: 11830488). It is absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This intronic variant (in intron 5) is located in reference to the exon at positions +3 for donor splice site and has a predicted decrease in the score of the canonical splice site by at least 75% (measured by both MES and SSF). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 11830488). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PP1_Strong, PM2_supporting, PP3, PS4_Supporting.

Met criteria codes

• PS3: RT-PCR assay demonstrates the use of a cryptic splice donor site resulted in frameshift, PMID: 11830488.
• PP1_Strong: 8 meioses in a family with FPD/AML.
• PS4_Supporting: One family with FPD/AML.
• PP3: Intronic variant (in introns 5) located in reference to exon at positions +3 for donor splice site and have a predicted decrease in the score of the canonical splice site by at least 75% (measured by both MES and SSF)
• PM2_Supporting: The variant is absent from all population databases.

Not Met criteria codes

• BA1: 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
• BS3: 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
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline