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 computer assertion could be determined for this classification!

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
Link to MONDO
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
More

Pathogenic

Met criteria codes 5
PM2_Supporting PP3 PS4_Supporting PP1_Strong PS3
Not Met criteria codes 21
PP4 PP2 PM6 PM3 PM5 PM1 PM4 BS2 BS4 BS1 BS3 BP5 BP7 BP2 BP3 BP4 BP1 PVS1 PS2 PS1 BA1

Evidence Links 1

Expert Panel

Criteria Specification Information

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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
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
PM2_Supporting
The variant is absent from all population databases.
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)
PS4_Supporting
One family with FPD/AML.
One family with FPD/AML. PubMed:11830488
PP1_Strong
8 meioses in a family with FPD/AML.
8 meioses in a family with FPD/AML. PubMed:11830488
PS3
RT-PCR assay demonstrates the use of a cryptic splice donor site resulted in frameshift, PMID: 11830488.
A 1-bp deletion in the splice donor site of intron 5 of the RUNX1 gene. The novel transcript resulting from use of a cryptic donor site resulted in frameshift after amino acid 135, addition of 41 unrelated residues, and termination at codon 177 (Arg135fsTer177). PubMed:11830488
Not Met criteria codes
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
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
8 meioses in a family with FPD/AML. PubMed:11830488
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
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
PVS1
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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