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]
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  • See Evidence submitted by expert panel for details.

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

CA248618

14466 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d7a48ae9-bd50-426d-bb9f-589c53013a9b

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
NM_001001890.2:c.427+3del
NM_001122607.1:c.427+3del
NM_001754.4: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

Pathogenic

Met criteria codes 5
PS3 PP1_Strong PP3 PS4_Supporting PM2
Not Met criteria codes 13
PVS1 BS3 BS1 BS4 BP4 BP2 BP7 PS1 BA1 PM4 PM1 PM5 PM6

Evidence Links 1

Expert Panel

Criteria Specification Information

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 completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This intronic variant (in intron 5) is located in reference to the 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). 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, PP3, PS4_Supporting.
Met criteria codes
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
PP1_Strong
8 meioses in a family with FPD/AML.
8 meioses in a family with FPD/AML. PubMed:11830488
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
PM2
The variant is absent from all population databases.
Not Met criteria codes
PVS1
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
BS4
8 meioses in a family with FPD/AML. PubMed:11830488
BP4
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
BP7
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
PM4
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
PM5
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
Approved on: 2019-08-01
Published on: 2019-08-02
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