Variant classification summary

NM_001754.4:c.177C>T

RUNX1 · NP_001745.2:p.(Gly59=) · NM_001754.4

GRCh37: chr21:36259314 G>A · GRCh38: chr21:34887017 G>A

Gene: RUNX1 Transcript: NM_001754.4

Final call

Likely Benign

BP4 supporting BP6 supporting benign BP7 supporting

Variant details

Gene

RUNX1

Transcript

NM_001754.4

Protein

NP_001745.2:p.(Gly59=)

gnomAD AF

3.745449279125862e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: BP4 is met because SpliceAI maximum delta 0.026 is below the VCEP cutoff of 0.20.

2

Likely Benign: BP6 is met based on the expert-panel Likely benign classification recorded in the adjudicated evidence.

3

Likely Benign: BP7 is met because the synonymous exon 4 variant is outside excluded splice-adjacent positions and SpliceAI maximum delta is 0.026.

Final determination: Under the RUNX1 VCEP Version 3.1 point-based framework, BP4, BP6, and BP7 each contribute -1 point for a total of -3, which maps to Likely Benign.

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	N/A	Not applicable: c.177C>T is synonymous at Gly59, with no protein-length change and SpliceAI maximum delta 0.026.	cspec pvs1_variant_assessment spliceai vcep_myeloid_malignancy_vcep_runx1_pilot_results
PS1	N/A	Not applicable: p.(Gly59=) is synonymous and therefore has no altered amino-acid change to match a pathogenic missense variant.	cspec vcep_myeloid_malignancy_vcep_runx1_pilot_results
PS2	Not assessed	Not assessed: no proven de novo occurrence with confirmed maternity and paternity and FPD/AML phenotype is documented for this variant.	cspec vcep_myeloid_malignancy_vcep_runx1_pilot_results
PS3	Not assessed	Not assessed: no variant-specific transactivation or secondary-assay result is available to evaluate the VCEP's altered-function requirement.	cspec
PS4	Not assessed	Not assessed: no validated proband count meeting RUNX1 phenotypic criteria was available, and the governing pilot-results table has no matching c.177C>T entry.	cspec vcep_myeloid_malignancy_vcep_runx1_pilot_results
PM1	N/A	Not applicable: residue 59 lies outside the VCEP-approved PM1 region, residues 89-204 within the RUNX1 RHD.	cspec vcep_myeloid_malignancy_vcep_runx1_pilot_results
PM2	Not assessed	Not assessed: gnomAD v4.1 GrpMax FAF is 1.83e-06 versus the ≤0.00005 threshold, but required 20x positional coverage is unreported.	cspec gnomad_v4 gnomad_v2 vcep_myeloid_malignancy_vcep_runx1_pilot_results
PM3	N/A	Not applicable: the RUNX1 VCEP specification explicitly designates PM3 as not applicable.	cspec
PM4	N/A	Not applicable: the synonymous p.(Gly59=) variant has neither an in-frame indel nor a stop-loss protein extension.	cspec pvs1_variant_assessment vcep_myeloid_malignancy_vcep_runx1_pilot_results
PM5	N/A	Not applicable: PM5 requires a missense change, whereas c.177C>T is synonymous and produces p.(Gly59=).	cspec vcep_myeloid_malignancy_vcep_runx1_pilot_results
PM6	Not assessed	Not assessed: no assumed de novo occurrences in patients with FPD/AML phenotype are documented for this variant.	cspec vcep_myeloid_malignancy_vcep_runx1_pilot_results
PP1	Not assessed	Not assessed: no countable genotype- and phenotype-positive family meioses or obligate carriers are documented for this variant.	cspec vcep_myeloid_malignancy_vcep_runx1_pilot_results
PP2	N/A	Not applicable: the RUNX1 VCEP explicitly excludes PP2 because RUNX1 does not meet its missense-constraint requirement.	cspec
PP3	Not met	Not met: SpliceAI maximum delta 0.026 is below the VCEP synonymous-variant PP3 threshold of 0.38.	cspec spliceai vcep_myeloid_malignancy_vcep_runx1_pilot_results
PP4	N/A	Not applicable: the RUNX1 VCEP rejects PP4 because FPD/AML is too nonspecific and has multiple possible genetic and environmental causes.	cspec
PP5	N/A	Not applicable: the RUNX1 VCEP explicitly prohibits PP5 under the ClinGen SVI VCEP Review Committee recommendation.	cspec
BA1	Not met	Not met: gnomAD v4.1 maximum continental AF is 5.09e-06, far below the VCEP BA1 threshold of 0.0015, despite six observed alleles.	cspec gnomad_v4 vcep_myeloid_malignancy_vcep_runx1_pilot_results
BS1	Not met	Not met: the highest gnomAD v4.1 continental AF is 5.09e-06, below the VCEP BS1 lower bound of 0.00015.	cspec gnomad_v4 gnomad_v2 vcep_myeloid_malignancy_vcep_runx1_pilot_results
BS2	N/A	Not applicable: the RUNX1 VCEP explicitly marks BS2 Not Applicable, regardless of the observed zero gnomAD homozygotes.	cspec vcep_myeloid_malignancy_vcep_runx1_pilot_results
BS3	Not assessed	Not assessed: no variant-specific transactivation result in the 80-115% wild-type range or normal secondary-assay result is available.	cspec
BS4	Not assessed	Not assessed: no genotype-negative, phenotype-positive relatives or at least 2 informative meioses are documented for this variant.	cspec vcep_myeloid_malignancy_vcep_runx1_pilot_results
BP1	N/A	Not applicable: the RUNX1 VCEP states that both truncating and missense variants cause FPD/AML, so BP1 does not apply.	cspec
BP2	Not assessed	Not assessed: no documented cis/trans phase or pathogenic variant in cis or trans is available to evaluate the VCEP BP2 rule.	cspec
BP3	N/A	Not applicable: the RUNX1 VCEP specification explicitly designates BP3 as not applicable for this synonymous variant.	cspec pvs1_variant_assessment vcep_myeloid_malignancy_vcep_runx1_pilot_results
BP4	Met	Met: SpliceAI maximum delta 0.026 is below the VCEP synonymous-variant BP4 cutoff of 0.20.	cspec spliceai vcep_myeloid_malignancy_vcep_runx1_pilot_results
BP5	N/A	Not applicable: the RUNX1 VCEP explicitly states that BP5 is not applicable despite rare patients carrying two hematologic-malignancy predisposition variants.	cspec
BP6	Met	Not applicable: the RUNX1 VCEP explicitly prohibits BP6 under the ClinGen SVI VCEP Review Committee recommendation.	cspec clinvar
BP7	Met	Met: synonymous exon-4 variant has SpliceAI maximum delta 0.026, satisfying the VCEP BP7 cutoff of 0.20 outside excluded splice-adjacent positions.	cspec spliceai vcep_myeloid_malignancy_vcep_runx1_pilot_results

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.