NM_001001890.2:c.1332_1334delinsG

RUNX1 · NP_001001890.1:p.(Leu445GlyfsTer127) · NM_001001890.2

GRCh37: chr21:36164460 AGG>C · GRCh38: chr21:34792163 AGG>C

Gene: RUNX1 Transcript: NM_001001890.2

Final call

Likely Pathogenic

PVS1 strong PM2 supporting PM5 supporting PP5 supporting

Variant details

Gene

RUNX1

Transcript

NM_001001890.2

Protein

NP_001001890.1:p.(Leu445GlyfsTer127)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The RUNX1 c.1332_1334delinsG (p.Leu445GlyfsTer127) variant has been reported in ClinVar, including a Likely Pathogenic expert-panel classification by the ClinGen Myeloid Malignancy VCEP.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the RUNX1 PM2_Supporting threshold of 0.00005.

This is a RUNX1 frameshift variant in a gene with an established loss-of-function disease mechanism, supporting use of the RUNX1 PVS1 framework, although the distal position suggests a downgraded rather than full very-strong PVS1 strength.

SpliceAI predicts no significant splice impact for this variant, with a max delta score of 0.00, which supports the RUNX1 PM5_Supporting rule for downstream nonsense or frameshift variants and does not support PP3 or BP4 application for this frameshift event.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework yields a total score of 7, which maps to Likely Pathogenic 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	Met	This variant is a RUNX1 frameshift variant in a gene with an established loss-of-function disease mechanism. Because the frameshift occurs near the 3' end and is predicted to alter the terminal portion of the protein rather than undergo classic nonsense-mediated decay, a downgraded PVS1 strength is appropriate under the RUNX1-specific framework; PVS1_Strong is supported pending manual confirmation of distal-region handling.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 is not applicable because this is a frameshift variant, not a variant producing the same established amino acid substitution as a previously classified pathogenic or likely pathogenic variant.	cspec
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 cannot be applied from the available evidence.	cspec clinvar
PS3	N/A	No variant-specific functional assay data were identified here, and the RUNX1 specification states that PS3 is not applied when the variant already meets PVS1.	cspec
PS4	Not assessed	This variant is reported in ClinVar, including an expert-panel classification, but the available evidence does not provide a verified count of affected probands meeting RUNX1 phenotypic criteria. PS4 therefore cannot be independently applied from the reviewed materials.	cspec clinvar
PM1	N/A	PM1 is not applicable because this variant is not a missense change affecting the RUNX1 runt homology domain hotspot residues defined by the RUNX1 specification.	cspec
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 because the RUNX1 phenotype framework is not evaluated as a recessive disorder in this specification.	cspec
PM4	N/A	PM4 is not applicable because this variant is a frameshift, whereas the RUNX1 PM4 rule is intended for in-frame insertions/deletions in the runt homology domain or for stop-loss variants causing a protein extension.	cspec
PM5	Met	Under the RUNX1 specification, PM5_Supporting can be applied to nonsense and frameshift variants downstream of c.98. This variant is a downstream frameshift, SpliceAI predicts no significant splice effect with a max delta score of 0.00, and PM1 does not apply, so PM5_Supporting is met.	cspec spliceai
PM6	Not assessed	No assumed de novo occurrences without full parentage confirmation were identified for this variant, so PM6 cannot be applied from the available evidence.	cspec clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be applied.	cspec
PP2	N/A	PP2 is not applicable in the RUNX1 specification.	cspec
PP3	N/A	PP3 is not applicable because this is not a missense, synonymous, or qualifying intronic variant under the RUNX1 computational rule. SpliceAI predicts no significant splice impact, with a max delta score of 0.00.	cspec spliceai
PP4	N/A	PP4 is not applicable in the RUNX1 specification because the associated phenotype is not considered sufficiently specific for this rule.	cspec
PP5	Met	Expert panel ClinGen Myeloid Malignancy Variant Curation Expert Panel classified as Likely pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the RUNX1 BA1 threshold of at least 0.0015.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the RUNX1 BS1 frequency range of 0.00015 to 0.0015.	cspec gnomad_v2 gnomad_v4
BS2	N/A	BS2 is not applicable in the RUNX1 specification.	cspec
BS3	Not assessed	No directly reviewed functional studies showing normal RUNX1 function for this variant were identified, so BS3 cannot be applied.	cspec oncokb
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 cannot be applied.	cspec
BP1	N/A	BP1 is not applicable in the RUNX1 specification.	cspec
BP2	Not assessed	No evidence was identified that this variant was observed in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant, so BP2 cannot be applied.	cspec
BP3	N/A	BP3 is not applicable in the RUNX1 specification.	cspec
BP4	N/A	BP4 is not applicable because this is not a missense, synonymous, or intronic variant within the RUNX1 BP4 computational framework. SpliceAI predicts no significant splice impact, with a max delta score of 0.00, but that alone does not make BP4 applicable to this frameshift variant.	cspec spliceai
BP5	N/A	BP5 is not applicable in the RUNX1 specification.	cspec
BP6	N/A	BP6 is not applicable because the RUNX1 VCEP does not use this criterion.	cspec
BP7	N/A	BP7 is not applicable because this variant is neither synonymous nor intronic under the RUNX1 BP7 rule.	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.