Variant classification summary

NM_001001890.2:c.569G>A

RUNX1 · NP_001001890.1:p.(Gly190Glu) · NM_001001890.2

GRCh37: chr21:36206862 C>T · GRCh38: chr21:34834565 C>T

Gene: RUNX1 Transcript: NM_001001890.2

Final call

VUS

PM1 supporting PM2 supporting

Variant details

Gene

RUNX1

Transcript

NM_001001890.2

Protein

NP_001001890.1:p.(Gly190Glu)

gnomAD AF

3.9891176869500004e-06 (v2.1)

ClinVar

Uncertain Significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The RUNX1 c.569G>A (p.Gly190Glu) variant has been reported in ClinVar, including an expert-panel assertion of uncertain significance.

2

This variant is absent from gnomAD v4.1 and is present only once in gnomAD v2.1 (1/250682 alleles; AF 3.98912e-06, 0.00040%), which supports rarity under the RUNX1 PM2_Supporting threshold of 0.00005.

3

The altered residue lies within the RUNX1 Runt homology domain residue range 89-204, supporting PM1 at supporting strength, but it is not one of the codons specified for PM1_Strong.

4

Computational evidence is mixed but does not meet RUNX1 VCEP thresholds for either PP3 or BP4: REVEL is 0.666, BayesDel is 0.313044, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.01.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework yields a total score of 2, which maps to VUS 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 missense variant does not fall into the RUNX1 loss-of-function categories used for PVS1, and SpliceAI predicts no significant splice effect (max delta score 0.01), so available evidence does not support a null-variant mechanism for this allele.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not met	No evidence was identified that this amino acid change is the same protein consequence as a previously established pathogenic or likely pathogenic RUNX1 variant from a different nucleotide change.	cspec clinvar
PS2	Not assessed	No proven de novo occurrence with confirmed maternity and paternity was identified for this variant, so PS2 cannot be assessed from the available evidence.	cspec
PS3	Not assessed	No variant-specific functional study demonstrating abnormal RUNX1 transactivation or corroborating abnormal secondary assay evidence was identified, so PS3 cannot be assessed from the available evidence.	cspec oncokb
PS4	Not assessed	No confirmed count of unrelated probands meeting RUNX1 phenotype criteria was identified for this variant, so PS4 cannot be assessed from the available evidence.	cspec clinvar
PM1	Met	This missense variant affects RUNX1 codon 190, which lies within the Runt homology domain residue range 89-204 used by the RUNX1 VCEP for PM1_Supporting. Codon 190 is not one of the 13 residues specified for PM1_Strong, so PM1 is met at supporting strength.	cspec
PM2	Met	This variant is absent from gnomAD v4.1 and is present only once in gnomAD v2.1 (1/250682 alleles; AF 3.98912e-06, 0.00040%), which is below the RUNX1 VCEP PM2_Supporting threshold of 0.00005, supporting rarity in the general population.	cspec gnomad_v2 gnomad_v4
PM4	N/A	This is a missense substitution, not an in-frame insertion/deletion or stop-loss variant, so RUNX1 PM4 does not apply.	cspec
PM5	N/A	RUNX1 PM5 cannot be used when PM1 is applied at any strength. Because this variant meets PM1_Supporting, PM5 is not applicable in this framework.	cspec pm5_candidates
PM6	Not assessed	No assumed de novo occurrences without full parentage confirmation were identified for this variant, so PM6 cannot be assessed from the available evidence.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed from the available evidence.	cspec
PP2	N/A	PP2 is not used by the RUNX1 VCEP.	cspec
PP3	Not met	Computational evidence does not meet the RUNX1 VCEP PP3 threshold. REVEL is 0.666, below the PP3 cutoff of 0.88, and SpliceAI is 0.01, below the splice threshold of 0.38. BayesDel is 0.313044, but RUNX1 PP3 is governed by the VCEP REVEL and SpliceAI thresholds.	cspec revel spliceai bayesdel
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 used by the RUNX1 VCEP.	cspec
BA1	Not met	Population frequency does not meet the RUNX1 BA1 threshold. The variant is absent from gnomAD v4.1 and is seen once in gnomAD v2.1, far below the BA1 threshold of 0.0015 (0.15%).	cspec gnomad_v2 gnomad_v4
BS1	Not met	Population frequency does not meet the RUNX1 BS1 threshold. The variant is absent from gnomAD v4.1 and the overall gnomAD v2.1 frequency is 3.98912e-06, which is below the BS1 range lower bound of 0.00015 (0.015%).	cspec gnomad_v2 gnomad_v4
BS2	N/A	BS2 is not applicable in the RUNX1 VCEP framework.	cspec
BS3	Not assessed	No variant-specific functional study demonstrating normal RUNX1 function was identified, so BS3 cannot be assessed from the available evidence.	cspec oncokb
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 cannot be assessed from the available evidence.	cspec
BP1	N/A	BP1 is not used by the RUNX1 VCEP.	cspec
BP2	Not assessed	No data were identified showing this variant in trans with a pathogenic variant or in cis with a pathogenic variant, so BP2 cannot be assessed from the available evidence.	cspec
BP3	N/A	BP3 is not applicable in the RUNX1 VCEP framework.	cspec
BP4	Not met	Computational evidence does not meet the RUNX1 VCEP BP4 threshold. Although SpliceAI is low at 0.01, REVEL is 0.666, which is not below the BP4 missense threshold of 0.50. BayesDel is available at 0.313044 but does not override the RUNX1 VCEP REVEL and SpliceAI rule.	cspec revel spliceai bayesdel
BP5	N/A	BP5 is not applicable in the RUNX1 VCEP framework.	cspec
BP6	N/A	BP6 is not used by the RUNX1 VCEP.	cspec
BP7	N/A	This is a missense variant, so BP7, which is restricted to synonymous and selected intronic variants in the RUNX1 VCEP framework, does not apply.	cspec
PM3	N/A	PM3 is not applicable in the RUNX1 VCEP framework.	cspec

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