Variant: NM_001754.5(RUNX1):c.351+1G>A

CA410203336

561236 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 603cd528-c485-4e30-934a-cabde6c6d80d

Approved on: 2024-03-26

Published on: 2024-03-26

HGVS expressions

NM_001754.5:c.351+1G>A
NM_001754.5(RUNX1):c.351+1G>A
NC_000021.9:g.34886842C>T
CM000683.2:g.34886842C>T
NC_000021.8:g.36259139C>T
CM000683.1:g.36259139C>T
NC_000021.7:g.35181009C>T
NG_011402.2:g.1102870G>A
ENST00000675419.1:c.351+1G>A
ENST00000300305.7:c.351+1G>A
ENST00000344691.8:c.270+1G>A
ENST00000358356.9:c.270+1G>A
ENST00000399237.6:c.315+1G>A
ENST00000399240.5:c.270+1G>A
ENST00000437180.5:c.351+1G>A
ENST00000455571.5:c.312+1G>A
ENST00000482318.5:c.59-6129G>A
NM_001001890.2:c.270+1G>A
NM_001122607.1:c.270+1G>A
NM_001754.4:c.351+1G>A
NM_001001890.3:c.270+1G>A
NM_001122607.2:c.270+1G>A

Pathogenic

• Met criteria codes: PM2_Supporting PM5_Supporting PS4_Moderate PVS1

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

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

The c.351+1G>A is a splice donor variant that is predicted to introduce exon 4 skipping and a frameshift with a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). This variant has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 27931139). 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: PVS1, PM2_supporting, PS4_Supporting, PM5_supporting.

Met criteria codes

• PM2_Supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).
• PM5_Supporting: This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting).
• PS4_Moderate: 2 probands (1 from PMID: 27931139 and 1 unpublished) meet RUNX1 phenotype criteria.
• PVS1: The c.351+1G>A is a splice donor variant that is predicted to introduce exon 4 skipping and a frameshift with a premature stop codon and expected to result in nonsense-mediated mRNA decay.

Not Met criteria codes

• PS2: No data currently available
• PS3: No data currently available
• PS1: This variant is not a missense, or synonymous variant.
• BP5: MM-VCEP deemed N/A for RUNX1
• BP7: This variant is not a synonymous or intronic variant.
• BP2: No evidence
• BP3: MM-VCEP deemed N/A for RUNX1
• BP4: This variant does not have applicable in-silico data available.
• BP1: MM-VCEP deemed N/A for RUNX1
• PP4: MM-VCEP deemed N/A for RUNX1
• PP3: This variant does not have applicable in-silico data available.
• PP2: MM-VCEP deemed N/A for RUNX1
• PP1: Not enough segregations (at least 3) reported in families in the literature to apply PP1.
• PM6: No data currently available
• PM3: MM-VCEP deemed N/A for RUNX1
• PM1: This variant is not a missense variant.
• PM4: This variant is not an in-frame deletion/insertion.
• BA1: This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.
• BS2: MM-VCEP deemed N/A for RUNX1
• BS3: No data currently available
• BS4: No evidence
• BS1: This variant does not have a MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental dataset.