Classification rationale

PM1PM2 VUS

RUNX1 c.569G>A

The RUNX1 c.569G>A (p.Gly190Glu) variant has been reported in ClinVar, including an expert-panel assertion of uncertain significance.¹ 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 0.00005.² 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.³ 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 0.01.⁴

PM1 + PM2 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 cspec ↗

4 revelbayesdelspliceai ↗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_001001890.2 · variants mapped to exon structure

RUNX1 NM_001001890.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 14 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 · 2

Strength Supporting Moderate Strong Very strong

PM1 supporting Pathogenic

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.

RUNX1 VCEP applies PM1_Supporting to missense variants affecting residues 89-204 within the Runt homology domain.RUNX1 VCEP reserves PM1_Strong for 13 specified residuescodon 190 is not on that list.

cspec ↗

PM2 supporting Pathogenic

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.

RUNX1 VCEP PM2_Supporting threshold is MAF <= 0.00005 with adequate population data.gnomAD v4.1: absent.gnomAD v2.1: 1/250682 alleles

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 6 not met · 8 not assessed

Pathogenic

PVS1 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.

PS1 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.

PS2 No proven de novo occurrence with confirmed maternity and paternity was identified for this variant, so PS2 cannot be assessed from the available evidence.

PS3 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.

PS4 No confirmed count of unrelated probands meeting RUNX1 phenotype criteria was identified for this variant, so PS4 cannot be assessed from the available evidence.

PM6 No assumed de novo occurrences without full parentage confirmation were identified for this variant, so PM6 cannot be assessed from the available evidence.

PP1 No segregation data were identified for this variant, so PP1 cannot be assessed from the available evidence.

PP3 Computational evidence does not meet the RUNX1 VCEP PP3 threshold.

Benign

BA1 Population frequency does not meet the RUNX1 BA1 threshold.

BS1 Population frequency does not meet the RUNX1 BS1 threshold.

BS3 No variant-specific functional study demonstrating normal RUNX1 function was identified, so BS3 cannot be assessed from the available evidence.

BS4 No non-segregation data were identified for this variant, so BS4 cannot be assessed from the available evidence.

BP2 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.

BP4 Computational evidence does not meet the RUNX1 VCEP BP4 threshold.

N/A · 12 PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BS2 · BP1 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.98912e-06; MAF= 0.00040%, 1/250682 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.83174e-06; MAF= 0.00088%, 1/113228 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

0.0004% · 1 / 250,682
0 hom

European (non-Finnish)

1 / 113,228

0.00088%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Uncertain Significance by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel). (ClinVarID = 3791471)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.666. BayesDel score = 0.313044.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RUNX1, a transcription factor involved in hematopoietic differentiation, is altered by mutation or chromosomal rearrangement in various hematologic ma

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

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

Triaged references · 12 PMIDs not cited in assessment

23619275 ↗ ACMG position statement on prenatal/preconception expanded carrier screening. CLINVAR

23652378 ↗ A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document. CLINVAR

25626707 ↗ Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes. CLINVAR

25730230 ↗ Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. CLINVAR

23169492 ↗ The perspective from EASAC and FEAM on direct-to-consumer genetic testing for health-related purposes. CLINVAR

24121147 ↗ Appropriateness of newborn screening for α1-antitrypsin deficiency. CLINVAR

22947299 ↗ Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening. CLINVAR

23037933 ↗ Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children. CLINVAR

23881473 ↗ Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors. CLINVAR

24022298 ↗ Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected]. CLINVAR

24394680 ↗ Parental permission for pilot newborn screening research: guidelines from the NBSTRN. CLINVAR

31022120 ↗ ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist. CLINVAR

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