Classification rationale

BP4BP6BP7 Likely Benign

RUNX1 c.444C>T

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.¹ 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 0.00015.² 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 0.20.³

BP4 + BP6 + BP7 → Likely Benign

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗cspec ↗

3 spliceai ↗cspec ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_001754.4 · variants mapped to exon structure

RUNX1 NM_001754.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 15 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

BP4 supporting Benign

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.

SpliceAI max delta score 0.01.

cspec ↗spliceai ↗

BP6 supporting Benign

Expert panel ClinGen Myeloid Malignancy Variant Curation Expert Panel classified as Likely benign.

Criterion listed as not applicable in the RUNX1 VCEP specification.ClinVar expert panel classification

cspec ↗clinvar ↗

BP7 supporting Benign

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.

Protein consequence p.(Thr148=).SpliceAI max delta score 0.01.

cspec ↗spliceai ↗

Assessed · not applied · 7 not met · 8 not assessed

Pathogenic

PVS1 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.

PS1 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.

PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant.

PS3 No published functional or RNA assay data were identified for this exact variant to show an abnormal RUNX1 effect.

PS4 No proband-level evidence was identified showing this variant in affected individuals at a frequency meeting the RUNX1 case-enrichment thresholds.

PM1 The identified change is synonymous and available evidence does not show that it affects a RUNX1 hotspot or pathogenic missense residue qualifying for PM1.

PM2 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.

PM6 No assumed de novo occurrences without full parental confirmation were identified for this variant.

PP1 No segregation data were identified showing this variant tracking with RUNX1-related disease in affected family members.

PP3 For RUNX1 synonymous variants, PP3 requires SpliceAI >= 0.38.

Benign

BA1 This variant does not meet the RUNX1 BA1 threshold.

BS1 This variant does not meet the RUNX1 BS1 threshold.

BS3 No well-established functional study was identified showing normal RUNX1 activity or normal splicing for this exact variant.

BS4 No non-segregation data were identified showing this variant in informative relatives who do not track with the RUNX1-related phenotype.

BP2 No evidence was identified that this variant is observed in trans with a pathogenic RUNX1 variant or in cis with another pathogenic variant.

N/A · 10 PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BS2 · BP1 · BP3 · BP5

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 7.68253e-05; MAF= 0.00768%, 124/1614052 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.98323e-05; MAF= 0.00898%, 106/1179976 alleles, homozygotes = 0); grpmax FAF= 7.574e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 5.65859e-05; MAF= 0.00566%, 16/282756 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.29411e-05; MAF= 0.00929%, 12/129114 alleles, homozygotes = 0); grpmax FAF= 6.015e-05.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0077% · 124 / 1,614,052
0 hom · FAF 0.0076%

European (non-Finnish) 106 / 1,179,976	0.009%
Remaining individuals 5 / 62,496	0.008%
African/African American 5 / 75,018	0.0067%
East Asian 2 / 44,886	0.0045%
South Asian 4 / 91,082	0.0044%
Ashkenazi Jewish 1 / 29,608	0.0034%
European (Finnish) 1 / 64,016	0.0016%

+ 3 not observed (Admixed American, Amish, Middle Eastern)

gnomAD v2.1

0.0057% · 16 / 282,756
0 hom · FAF 0.006%

European (non-Finnish) 12 / 129,114	0.0093%
African/African American 2 / 24,962	0.008%
South Asian 2 / 30,614	0.0065%

+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Likely Benign by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55872606, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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