LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-06
Case ID: NM_001001890.2_c.393T_C_20260506_063656
Framework: ACMG/AMP 2015
Variant classification summary

NM_001001890.2:c.393T>C

RUNX1  · NP_001001890.1:p.(Phe131=)  · NM_001001890.2
GRCh37: chr21:36252888 A>G  ·  GRCh38: chr21:34880591 A>G
Gene: RUNX1 Transcript: NM_001001890.2
Final call
Likely Benign
PM2 supporting BP4 supporting BP7 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
RUNX1
Transcript
NM_001001890.2
Protein
NP_001001890.1:p.(Phe131=)
gnomAD AF
ClinVar
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The RUNX1 NM_001001890.2:c.393T>C (p.(Phe131=)) variant has been reported in ClinVar, where the ClinGen Myeloid Malignancy Variant Curation Expert Panel classified the equivalent RUNX1 transcript representation as uncertain significance and one clinical laboratory classified it as likely benign.
2
This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (1/1614108 alleles; AF 6.20e-07), with the highest observed subpopulation frequency of 1.67e-05 remaining below the RUNX1 PM2_Supporting threshold of 0.00005.
3
Computational splicing prediction shows no significant splice impact, with a SpliceAI maximum delta score of 0.07, which supports BP4 and BP7 and does not meet the RUNX1 PP3 threshold.
Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework yields a total score of -1, which maps to Likely Benign under the specified Tavtigian-style ranges.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 Not met This synonymous variant does not fall within the RUNX1 loss-of-function variant categories used for PVS1, and available splicing prediction does not support a splice-disrupting effect. It is not a nonsense, frameshift, or canonical +/-1,2 splice variant, and SpliceAI shows a maximum delta score of 0.07.
cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1 Not met No evidence was identified that this variant produces the same established pathogenic or likely pathogenic amino acid or splice effect as another RUNX1 variant.
cspec clinvar
PS2 Not assessed No confirmed de novo occurrence with maternity and paternity established was identified for this variant.
cspec
PS3 Not assessed No published functional study was identified showing an abnormal effect of this specific variant on RUNX1 transactivation, secondary functional assays, or splicing.
cspec oncokb
PS4 Not assessed This variant has been reported in ClinVar, but the available evidence does not document the number of unrelated affected probands meeting RUNX1 phenotypic criteria that would be required for PS4.
cspec clinvar
PM1 Not met This synonymous variant does not meet the RUNX1 PM1 rule, which is specified for protein-altering variants affecting defined critical residues or other amino acids within the Runt homology domain.
cspec hotspots
PM2 Met This variant is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1 (1/1614108 alleles; AF 6.20e-07). The highest observed subpopulation frequency is 1/60016 in Admixed American individuals (AF 1.67e-05), which is below the RUNX1 PM2_Supporting threshold of 0.00005.
cspec gnomad_v2 gnomad_v4
PM4 Not met This variant is a synonymous substitution and does not cause an in-frame insertion/deletion or stop-loss protein extension, so PM4 is not met.
cspec
PM5 Not met This variant is synonymous and does not represent a missense change at a residue with previously established pathogenic missense variation. The special RUNX1 PM5 extension for truncating variants downstream of c.98 also does not apply.
cspec
PM6 Not assessed No assumed de novo occurrence was identified for this variant.
cspec
PP1 Not assessed No segregation data were identified for this variant in affected relatives.
cspec
PP3 Not met For synonymous RUNX1 variants, PP3 requires SpliceAI >=0.38. This variant has a SpliceAI maximum delta score of 0.07, which is below that threshold and does not support a predicted splice-disrupting effect.
cspec spliceai
BA1 Not met The observed population frequency is far below the RUNX1 BA1 threshold. In gnomAD v4.1 the highest observed subpopulation frequency is 1.67e-05, which is below the BA1 threshold of 0.0015.
cspec gnomad_v4
BS1 Not met The observed population frequency does not reach the RUNX1 BS1 range. In gnomAD v4.1 the highest observed subpopulation frequency is 1.67e-05, which is below the BS1 lower bound of 0.00015.
cspec gnomad_v4
BS3 Not assessed No functional study was identified showing normal splicing or other normal function for this specific variant.
cspec oncokb
BS4 Not assessed No nonsegregation data were identified for this variant.
cspec
BP2 Not assessed No evidence was identified that this variant occurs in trans with a pathogenic RUNX1 variant, in cis with a pathogenic variant, or in a homozygous state in an unaffected context.
cspec
BP4 Met For synonymous RUNX1 variants, BP4 is met when SpliceAI is <=0.20. This variant has a SpliceAI maximum delta score of 0.07, supporting no significant predicted splice impact.
cspec spliceai vcep_myeloid_malignancy_vcep_runx1_pilot_results
BP7 Met This variant is synonymous, lies within exon 2 and not within the last 3 nucleotides before a donor site or the first nucleotide after an acceptor site, and SpliceAI predicts no significant splice impact (maximum delta score 0.07). These findings meet the RUNX1 BP7 rule.
cspec spliceai vcep_myeloid_malignancy_vcep_runx1_pilot_results
PP4 N/A PP4 is not applicable in the RUNX1 MM-VCEP framework because the FPD/AML phenotype is considered insufficiently specific for use of this criterion.
cspec
PP5 N/A PP5 is not applicable in this VCEP framework.
cspec
BP1 N/A BP1 is not applicable in this VCEP framework.
cspec
BP3 N/A BP3 is not applicable in this VCEP framework.
cspec
BP5 N/A BP5 is not applicable in this VCEP framework.
cspec
BP6 N/A BP6 is not applicable in this VCEP framework.
cspec
BS2 N/A BS2 is not applicable in this VCEP framework.
cspec
PP2 N/A PP2 is not applicable in this VCEP framework.
cspec
PM3 N/A PM3 is not applicable in this VCEP framework.
cspec
Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.