Variant: NM_001754.5(RUNX1):c.*2840A>T

CA10653553

339818 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 808f8d7b-6023-415d-bce5-e3b50e3d2a6d

Approved on: 2023-11-13

Published on: 2023-11-13

HGVS expressions

NM_001754.5:c.*2840A>T
NM_001754.5(RUNX1):c.*2840A>T
NC_000021.9:g.34789295T>A
CM000683.2:g.34789295T>A
NC_000021.8:g.36161592T>A
CM000683.1:g.36161592T>A
NC_000021.7:g.35083462T>A
NG_011402.2:g.1200417A>T
ENST00000675419.1:c.*2840A>T
ENST00000300305.7:c.*2840A>T
ENST00000344691.8:c.*2840A>T
ENST00000437180.5:c.*2840A>T
NM_001001890.2:c.*2840A>T
NM_001754.4:c.*2840A>T
NM_001001890.3:c.*2840A>T

Benign

• Met criteria codes: BS1 BP7 BP4

• Not Met criteria codes: BA1 PM6 PM2 PM1 PM5 PM3 PM4 BS4 BS3 BS2 BP5 BP2 BP3 BP1 PVS1 PS2 PS4 PS3 PS1 PP1 PP4 PP3 PP2

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.*2840A>T is an intronic variant. Highest MAF at 0.0002 (0.02%, 3/15346,) in the European (Non-Finnish) subpopulation of gnomAD v2 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%). Including alleles from gonmAD v3, variant present in ≥ 5 alleles (BS1). REVEL Score is not applicable and SpliceAI ≤0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.311 < 2.0). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7

Met criteria codes

• BS1: Highest MAF at 0.0002 (0.02%, 3/15346,) in the European (Non-Finnish) subpopulation of gnomAD v2 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%). Including alleles from gonmAD v3, variant present in ≥ 5 alleles.
• BP7: Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.311 < 2.0)
• BP4: This 3'UTR variant has a SpliceAI score ≤ 0.20 (Donor Gain 0.00).

Not Met criteria codes

• BA1: Highest MAF is less than 0.0015 (0.15%) at 0.0002 (0.02%, 3/15346,) in the European (Non-Finnish) subpopulation of gnomAD v2 cohort. Including alleles found in gnomAD v3, variant present in ≥ 5 alleles.
• PM6: This variant has not been reported in probands in the literature.
• PM2: Variant is present in database (gnomAD) with at least 20x coverage for RUNX1 t 0.0002 (0.02%, 3/15346,) in the European (Non-Finnish) subpopulation of gnomAD v2 cohort
• PM1: This variant does not affect any of the following amino acid residues, nor is it located within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 NOR is it within residues 89-204
• PM5: This is not a missense variant, and there has not yet been a different missense change determined to be pathogenic at this amino acid residue.
• PM3: This rule is not applicable for MM-VCEP
• PM4: This variant does not affect one of the other residues within the RHD.
• BS4: This variant has not been reported in probands
• BS3: This variant has not been featured in in vitro or in vivo functional studies showing no damaging effect on the gene or gene product.
• BS2: This rule is not applicable for MM-VCEP
• BP5: This rule is not applicable for MM-VCEP
• BP2: This variant has not been detected in a homozygous state in an individual or in a population database (gnomAD). 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
• BP1: This rule is not applicable for MM-VCEP
• PVS1: not a null variant
• PS2: This variant has not been reported in probands in the literature.
• PS4: This variant has not been reported in probands.
• 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 is a noncoding variant.
• PP1: This variant was not found to co-segregate with disease in multiple affected family members.
• PP4: This rule is not applicable for MM-VCEP
• PP3: This UTR variant does not have a SpliceAI score of ≥ 0.38 (Donor Gain 0.00).
• PP2: This rule is not applicable for MM-VCEP