Variant classification summary

NM_001754.4:c.444C>T

RUNX1 · NP_001745.2:p.(Thr148=) · NM_001754.4

GRCh37: chr21:36252918 G>A · GRCh38: chr21:34880621 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.(Thr148=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The RUNX1 c.444C>T (p.Thr148=) variant is reported in ClinVar and is currently classified as Likely Benign by the ClinGen Myeloid Malignancy Variant Curation Expert Panel.

2

This variant is present in population databases, including gnomAD v4.1 with grpmax FAF 7.574e-05 and gnomAD v2.1 with grpmax FAF 6.015e-05; these values are above the RUNX1 PM2_Supporting threshold of 0.00005 and below the RUNX1 BS1 threshold of 0.00015.

3

In silico splicing prediction does not support a splice-disrupting effect, with SpliceAI max delta score 0.01, which is below the RUNX1 PP3 threshold of 0.38 and within the BP4 and BP7 benign threshold of 0.20.

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 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	RUNX1 loss of function is an established disease mechanism, but this synonymous variant is not a nonsense, frameshift, or canonical +/-1,2 splice variant, and no abnormal RNA evidence was identified to support a loss-of-function effect.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not met	This synonymous variant does not create an amino acid substitution, and no evidence was identified that it causes the same predicted splice effect as an established pathogenic or likely pathogenic RUNX1 variant.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified for this variant.	cspec clinvar
PS3	Not assessed	No published functional or RNA assay data were identified for this exact variant to show an abnormal RUNX1 effect.	cspec oncokb
PS4	Not assessed	No proband-level evidence was identified showing this variant in affected individuals at a frequency meeting the RUNX1 case-enrichment thresholds.	cspec clinvar
PM1	Not met	The identified change is synonymous and available evidence does not show that it affects a RUNX1 hotspot or pathogenic missense residue qualifying for PM1.	cspec hotspots
PM2	Not met	This variant is present in gnomAD v4.1 with grpmax FAF 7.574e-05, which is above the RUNX1 PM2_Supporting threshold of 0.00005; gnomAD v2.1 also shows grpmax FAF 6.015e-05, above that threshold.	cspec gnomad_v4 gnomad_v2
PM3	N/A	PM3 is not used in the RUNX1 VCEP framework.	cspec
PM4	N/A	This variant is neither an in-frame insertion/deletion nor a stop-loss variant, so PM4 does not apply.	cspec
PM5	N/A	This variant is synonymous rather than missense, so the RUNX1 PM5 missense-residue framework does not apply.	cspec
PM6	Not assessed	No assumed de novo occurrences without full parental confirmation were identified for this variant.	cspec clinvar
PP1	Not assessed	No segregation data were identified showing this variant tracking with RUNX1-related disease in affected family members.	cspec clinvar
PP2	N/A	PP2 is not used in the RUNX1 VCEP framework.	cspec
PP3	Not met	For RUNX1 synonymous variants, PP3 requires SpliceAI >= 0.38. This variant has a SpliceAI max delta score of 0.01, which is below that threshold and does not support a predicted splice-disrupting effect.	cspec spliceai
PP4	N/A	PP4 is not applicable in the RUNX1 VCEP framework because the associated phenotype is not considered sufficiently specific for this criterion.	cspec
PP5	N/A	PP5 is not used in the RUNX1 VCEP framework.	cspec
BA1	Not met	This variant does not meet the RUNX1 BA1 threshold. The highest observed population frequency is 8.98323e-05 in gnomAD v4.1 European non-Finnish individuals, which is below the BA1 threshold of 0.0015.	cspec gnomad_v4 gnomad_v2
BS1	Not met	This variant does not meet the RUNX1 BS1 threshold. The highest observed population frequency is 8.98323e-05 in gnomAD v4.1 European non-Finnish individuals, which is below the BS1 lower threshold of 0.00015.	cspec gnomad_v4 gnomad_v2
BS2	N/A	BS2 is not applicable in the RUNX1 VCEP framework.	cspec
BS3	Not assessed	No well-established functional study was identified showing normal RUNX1 activity or normal splicing for this exact variant.	cspec oncokb
BS4	Not assessed	No non-segregation data were identified showing this variant in informative relatives who do not track with the RUNX1-related phenotype.	cspec clinvar
BP1	N/A	BP1 is not used in the RUNX1 VCEP framework.	cspec
BP2	Not assessed	No evidence was identified that this variant is observed in trans with a pathogenic RUNX1 variant or in cis with another pathogenic variant.	cspec clinvar
BP3	N/A	BP3 is not applicable in the RUNX1 VCEP framework.	cspec
BP4	Met	For RUNX1 synonymous variants, BP4 applies when SpliceAI is <= 0.20. This variant has a SpliceAI max delta score of 0.01, which is below that threshold and supports no meaningful predicted splice effect.	cspec spliceai
BP5	N/A	BP5 is not applicable in the RUNX1 VCEP framework.	cspec
BP6	Met	Expert panel ClinGen Myeloid Malignancy Variant Curation Expert Panel classified as Likely benign.	cspec clinvar
BP7	Met	This is a synonymous RUNX1 variant with SpliceAI max delta score 0.01, which is below the BP7 threshold of 0.20, and it does not fall in the excluded near-canonical splice positions specified by the RUNX1 VCEP rule.	cspec spliceai

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