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_001754.5(RUNX1):c.258G>A (p.Pro86=)

CA320642685

1007447 (ClinVar)

Gene: RUNX1 (HGNC:861)
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome (MONDO:0011071)
Inheritance Mode: Autosomal dominant inheritance
UUID: 8520e779-0fdc-4c15-989a-682dc4e1c6e6
Approved on: 2024-07-11
Published on: 2024-07-11

HGVS expressions

NM_001754.5(RUNX1):c.258G>A (p.Pro86=)
NM_001754.5:c.258G>A
NC_000021.9:g.34886936C>T
CM000683.2:g.34886936C>T
NC_000021.8:g.36259233C>T
CM000683.1:g.36259233C>T
NC_000021.7:g.35181103C>T
NG_011402.2:g.1102776G>A
ENST00000675419.1:c.258G>A
ENST00000300305.7:c.258G>A
ENST00000344691.8:c.177G>A
ENST00000358356.9:c.177G>A
ENST00000399237.6:c.222G>A
ENST00000399240.5:c.177G>A
ENST00000437180.5:c.258G>A
ENST00000455571.5:c.219G>A
ENST00000482318.5:c.59-6223G>A
NM_001001890.2:c.177G>A
NM_001122607.1:c.177G>A
NM_001754.4:c.258G>A
NM_001001890.3:c.177G>A
NM_001122607.2:c.177G>A
More

Likely Benign

Met criteria codes 2
BP7 BP4
Not Met criteria codes 21
PVS1 BS4 BS3 BS1 BP5 BP2 BP3 BP1 PS4 PS3 PS1 BA1 PP1 PP4 PP3 PP2 PM2 PM3 PM1 PM4 PM5

Evidence Links 0

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
NM_001754.5:c.258G>A (p.Pro86=) is a synonymous variant which is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by its phyloP score (BP4, BP7). The germline variant has not been reported in patients meeting the RUNX1 phenotypic criteria and has been identified at an overall minor allele frequency of 0.0077% (1/13002 alleles) in ESP. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, BP7.
Met criteria codes
BP7
This synonymous variant is predicted by MES and SpliceAI to lead to either no change/an increase/a decrease by no more than 10% in the canonical splice site score and no putative cryptic splice sites are created (SSF-like predicts the creation of a cryptic donor splice site at c.259). An evolutionary conservation algorithm predicts the site as being weakly conserved (PhyloP score = -3.22807 in GRCh38), but the variant allele is not the reference nucleotide in one primate and/or three mammal species.
BP4
SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS3
No relevant data found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS1
Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3), but is present in 1/6501 individuals in ESP.
BP5
Not applicable
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
Not applicable
BP1
Not applicable
PS4
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS3
No relevant data found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3), but is present in 1/6501 individuals in ESP.
PP1
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PP4
Not applicable
PP3
SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
PP2
Not applicable
PM2
Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3), but is present in 1/6501 individuals in ESP.
PM3
Not applicable
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
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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