Variant: NM_001754.5(RUNX1):c.508+1G>C

CA410202462

1299484 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 5254a3a7-a1c1-442e-9626-0f05a68c4437

Approved on: 2025-01-15

Published on: 2025-01-15

HGVS expressions

NM_001754.5:c.508+1G>C
NM_001754.5(RUNX1):c.508+1G>C
NC_000021.9:g.34880556C>G
CM000683.2:g.34880556C>G
NC_000021.8:g.36252853C>G
CM000683.1:g.36252853C>G
NC_000021.7:g.35174723C>G
NG_011402.2:g.1109156G>C
ENST00000675419.1:c.508+1G>C
ENST00000300305.7:c.508+1G>C
ENST00000344691.8:c.427+1G>C
ENST00000358356.9:c.427+1G>C
ENST00000399237.6:c.472+1G>C
ENST00000399240.5:c.427+1G>C
ENST00000437180.5:c.508+1G>C
ENST00000482318.5:c.*98+1G>C
NM_001001890.2:c.427+1G>C
NM_001122607.1:c.427+1G>C
NM_001754.4:c.508+1G>C
NM_001001890.3:c.427+1G>C
NM_001122607.2:c.427+1G>C

Likely Pathogenic

• Met criteria codes: PVS1 PM2_Supporting

• Not Met criteria codes: PM1 PM5 PM3 PM4 PS2 PS4 PS3 PS1 BA1 PM6 PP1 PP4 PP3 PP2 BS4 BS3 BS1 BS2 BP7 BP5 BP2 BP3 BP4 BP1

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

NM_001754.5(RUNX1):c.508+1G>C is a dinucleotide splicing variant which results in the skipping of exon 5 (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, PVS1.

Met criteria codes

• PVS1: This splice site variant results in the skipping of Exon 5
• PM2_Supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).

Not Met criteria codes

• PM1: This variant is not a missense variant.
• PM5: This variant is not a missense, synonymous, or frameshift variant.
• PM3: This rule is not applicable for MM-VCEP.
• PM4: This variant is not an in-frame deletion/insertion.
• PS2: De novo data for this variant has not been reported in literature.
• PS4: Proband data for this variant has not been reported in literature. Variant detected as somatic variant only (PMID: 36380727).
• PS3: This variant has not been featured in in vitro or in vivo functional studies showing a damaging effect on the gene or gene product.
• PS1: This variant is not a missense, synonymous, or frameshift variant.
• BA1: This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.
• PM6: Assumed de novo data for this variant has not been reported in literature.
• PP1: Segregation data for this variant has not been reported in literature.
• PP4: This rule is not applicable for MM-VCEP.
• PP3: This variant has a SpliceAI score ≥ 0.38 (Donor Loss 1.00), but this variant does not have an available REVEL score, nor do multiple other predictors (X, X) predict a deleterious impact.
• PP2: This is not a missense variant.
• BS4: Segregation data for this variant has not been reported in literature.
• BS3: This variant has not been featured in in vitro or in vivo functional studies that show no damaging effect on protein function or splicing.
• BS1: This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.
• BS2: This rule is not applicable for MM-VCEP.
• BP7: Splicing predictions do not illustrate that this variant has no impact.
• BP5: This rule is not applicable for MM-VCEP.
• BP2: This variant has not been observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
• BP3: This rule is not applicable for MM-VCEP.
• BP4: This variant occurs at a canonical splice site so BP4 cannot be applied.
• BP1: This rule is not applicable for MM-VCEP.