Variant classification summary

NM_001001890.2:c.1113C>T

RUNX1 · NP_001001890.1:p.(Ala371=) · NM_001001890.2

GRCh37: chr21:36164681 G>A · GRCh38: chr21:34792384 G>A

Gene: RUNX1 Transcript: NM_001001890.2

Final call

Likely Benign

PM2 supporting BP4 supporting BP7 supporting

Variant details

Gene

RUNX1

Transcript

NM_001001890.2

Protein

NP_001001890.1:p.(Ala371=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The RUNX1 c.1113C>T (p.Ala371=; p.A371=) variant has been reported in ClinVar, where the aggregate record is Uncertain Significance with expert panel review and includes two likely benign laboratory submissions.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing the observed population frequency at 0 and below the RUNX1 PM2_supporting threshold of 0.00005.

3

SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, which is below the RUNX1 PP3 threshold of 0.38 and at or below the BP4 and BP7 threshold of 0.20 for synonymous variants.

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 is not a nonsense, frameshift, or canonical splice-site variant, and SpliceAI predicts no significant splice impact (max delta score 0.00). Available evidence does not support a loss-of-function effect for this variant.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	N/A	This synonymous variant does not create an altered amino acid, and no evidence was identified that it produces the same pathogenic splicing event as an established pathogenic or likely pathogenic variant. PS1 is not applicable on the current evidence.	cspec spliceai
PS2	Not assessed	No proven de novo occurrence with confirmed maternity and paternity was identified for this variant in a patient with a RUNX1-related phenotype.	clinvar cspec
PS3	Not assessed	No published functional study or RNA assay was identified showing an abnormal effect for this exact variant.	cspec
PS4	Not assessed	This variant is present in ClinVar, but no exact proband count meeting RUNX1 phenotypic criteria was identified to support case enrichment.	clinvar cspec
PM1	Not met	This variant is a synonymous change at Ala371, which is outside the RUNX1 Runt homology domain hotspot region defined for PM1 (residues 89-204). Available evidence does not support location in a critical hotspot or constrained functional residue used for PM1.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0, which is below the RUNX1 PM2_supporting threshold of 0.00005.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the RUNX1 VCEP framework.	cspec
PM4	N/A	This variant is a synonymous single-nucleotide substitution and is not an in-frame insertion/deletion or stop-loss variant, so PM4 is not applicable.	cspec
PM5	N/A	PM5 is intended for missense variants, and this variant is synonymous. No RUNX1-specific PM5 scenario applies on the current evidence.	cspec
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified for this variant in a patient with a RUNX1-related phenotype.	clinvar cspec
PP1	Not assessed	No segregation data were identified showing that this variant tracks with a RUNX1-related phenotype in informative meioses.	clinvar cspec
PP2	N/A	PP2 is not applicable in the RUNX1 VCEP framework.	cspec
PP3	Not met	For synonymous RUNX1 variants, PP3 requires SpliceAI at least 0.38. This variant has a SpliceAI maximum delta score of 0.00, which is below that threshold and does not support a predicted splice effect.	cspec spliceai
PP4	N/A	PP4 is not applicable in the RUNX1 VCEP framework because the RUNX1-associated phenotype is not considered sufficiently specific for this criterion.	cspec
PP5	N/A	PP5 is not for use in this VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD, so the observed population frequency is 0 and does not reach the RUNX1 BA1 threshold of at least 0.0015.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD, so the observed population frequency is 0 and does not fall within the RUNX1 BS1 range of 0.00015 to 0.0015.	cspec gnomad_v2 gnomad_v4
BS2	N/A	BS2 is not applicable in the RUNX1 VCEP framework.	cspec
BS3	Not assessed	No published RNA study or other functional assay was identified showing normal function for this exact variant.	cspec
BS4	Not assessed	No family data were identified showing that this variant fails to segregate with a RUNX1-related phenotype across informative meioses.	clinvar cspec
BP1	N/A	BP1 is not applicable in the RUNX1 VCEP framework.	cspec
BP2	Not assessed	No data were identified showing this variant in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant.	clinvar cspec
BP3	N/A	BP3 is not applicable in the RUNX1 VCEP framework.	cspec
BP4	Met	For synonymous RUNX1 variants, BP4 applies when SpliceAI is 0.20 or lower. This variant has a SpliceAI maximum delta score of 0.00, supporting no predicted splice impact.	cspec spliceai
BP5	N/A	BP5 is not applicable in the RUNX1 VCEP framework.	cspec
BP6	N/A	BP6 is not for use in this VCEP framework.	cspec
BP7	Met	This synonymous variant is not at a canonical splice-site boundary position used to exclude BP7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is at or below the RUNX1 BP7 threshold of 0.20.	cspec spliceai

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