Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001754.5(RUNX1):c.988T>G (p.Phe330Val)

CA410148771

1716418 (ClinVar)

Gene: RUNX1 (HGNC:861)

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome (MONDO:0011071)

Inheritance Mode: Autosomal dominant inheritance

UUID: 2b2ba19e-5dc8-415c-990c-f18727a398ba

Approved on: 2025-01-15

Published on: 2025-01-15

HGVS expressions

NM_001754.5(RUNX1):c.988T>G (p.Phe330Val)

NM_001754.5:c.988T>G

NC_000021.9:g.34792590A>C

CM000683.2:g.34792590A>C

NC_000021.8:g.36164887A>C

CM000683.1:g.36164887A>C

NC_000021.7:g.35086757A>C

NG_011402.2:g.1197122T>G

ENST00000675419.1:c.988T>G

ENST00000300305.7:c.988T>G

ENST00000344691.8:c.907T>G

ENST00000399240.5:c.715T>G

ENST00000437180.5:c.988T>G

ENST00000482318.5:c.*578T>G

NM_001001890.2:c.907T>G

NM_001754.4:c.988T>G

NM_001001890.3:c.907T>G

Uncertain Significance

PM2_Supporting BP4

PS3 PS4 PS2 PS1 BA1 PP1 PP3 PP2 PM3 PM1 PM5 PM6 PVS1 BS3 BS4 BS1 BP5 BP2 BP1

Evidence Links 0

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

NM_001754.5(RUNX1):c.988T>G (p.Phe330Val) is a missense variant which is absent from gnomAD v2 and v3 (PM2_supporting). This variant has not been reported in the literature. The computational predictor REVEL gives a score of 0.474, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_supporting and BP4.

PM2_Supporting

Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).

BP4

REVEL score = 0.474, which is less than the v2 threshold of 0.50. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).

PS3

No literature was found in LOVD, HGMD, ClinVar, COSMIC, and Mastermind.

PS4

No cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, and Mastermind.

PS2

No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, and Mastermind.

PS1

No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, and Mastermind.

BA1

Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).

PP1

No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, and Mastermind.

PP3

REVEL score = 0.474, which is not higher than the v2 threshold of 0.88. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).

PP2

Not applicable

PM3

Not applicable

PM1

Not located at a hotspot (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R210, R204) or within residues 89-204.

PM5

F330/F303 variants have not been reported in COSMIC or Mastermind.

PM6

No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, and Mastermind.

PVS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS3

No literature was found in LOVD, HGMD, ClinVar, COSMIC, and Mastermind.

BS4

No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, and Mastermind.

BS1

Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).

BP5

Not applicable

BP2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP1

Not applicable

Curation History

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