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RUNX1c.1094A>CUncertain significance
Print report
Variant interpretation report

RUNX1 c.1094A>C, p.(Gln365Pro)

NM_001001890.2:c.1094A>C NP_001001890.1:p.(Gln365Pro) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About RUNX1

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is ClinGen RUNX1 VCEP v3.1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and is also absent from gnomAD v4.1, with 0/1565090 alleles observed overall and 0/73964 alleles in the highest observed subpopulation. The observed frequency is below the RUNX1 VCEP PM2_Supporting threshold of 0.00005, so PM2_Supporting is met.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

For this missense variant, REVEL is 0.245, which is below the RUNX1 VCEP BP4 threshold of 0.50, and SpliceAI shows a maximum delta score of 0.00, which is at or below the BP4 threshold of 0.20. BayesDel is also negative at -0.122289, which does not support a damaging effect. These computational results support BP4.

Recorded classification: Uncertain significance

Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PM2 supporting (+1) + BP4 supporting (-1) = 0 points, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4 →
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen RUNX1 VCEP v3.1.0, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 5 not met · 10 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The RUNX1 NM_001001890.2:c.1094A>C (p.Gln365Pro, p.Q365P) variant has been reported in ClinVar and is currently classified there as a variant of uncertain significance by the ClinGen Myeloid Malignancy Variant Curation Expert Panel.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, with 0/1565090 alleles observed in gnomAD v4.1, which supports very low population frequency for RUNX1 disease.

Computational evidence does not support a damaging effect, with REVEL 0.245, SpliceAI maximum delta score 0.00, and BayesDel -0.122289; these findings support BP4 and do not support PP3.

Met · 2

PM2 SupportingThis variant is absent from gnomAD v2.1 and is also absent from gnomAD v4.1, with 0/1565090 alleles observed overall and 0/73964 alleles in the highest observed subpopulation. The observed frequency is below the RUNX1 VCEP PM2_Supporting threshold of 0.00005, so PM2_Supporting is met. Details ▾Hide ▴
Rule
RUNX1 VCEP PM2_Supporting
Evidence considered
  • gnomAD v2.1: absent.
  • gnomAD v4.1: 0/1565090 alleles
  • AF 0.0.
  • RUNX1 VCEP PM2_Supporting threshold is MAF <= 0.00005.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingFor this missense variant, REVEL is 0.245, which is below the RUNX1 VCEP BP4 threshold of 0.50, and SpliceAI shows a maximum delta score of 0.00, which is at or below the BP4 threshold of 0.20. BayesDel is also negative at -0.122289, which does not support a damaging effect. These computational results support BP4. Details ▾Hide ▴
Rule
RUNX1 VCEP BP4
Evidence considered
  • REVEL score 0.245.
  • SpliceAI max delta score 0.00.
  • BayesDel score -0.122289.
  • RUNX1 VCEP BP4 requires REVEL < 0.50 and SpliceAI <= 0.20 for missense variants.
Sources
cspec ↗revelspliceai ↗bayesdel

Not met · 5 · evaluated, threshold not reached

PVS1 This is a missense variant, not a nonsense, frameshift, or canonical splice-site variant, and SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.00. Available evidence does not support a loss-of-function mechanism for this specific change, so PVS1 is not met. Details ▾Hide ▴
Rule
RUNX1 VCEP PVS1 / generic PVS1 scaffold
Evidence considered
  • RUNX1 VCEP allows PVS1 for established loss-of-function contexts.
  • Variant-level PVS1 scaffold places this change outside default null-variant buckets.
  • SpliceAI max delta score is 0.00.
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessmentspliceai ↗
PM1 The RUNX1 VCEP PM1 region is restricted to residues 89-204 within the Runt homology domain, with stronger weighting for 13 specific residues. This variant affects p.Gln365Pro, which lies outside that region, so PM1 is not met. Details ▾Hide ▴
Rule
RUNX1 VCEP PM1
Evidence considered
  • RUNX1 VCEP PM1 applies to residues 89-204 in the Runt homology domain.
  • Variant affects residue 365.
Sources
cspec ↗
PP3 For this missense variant, REVEL is 0.245, which is below the RUNX1 VCEP PP3 threshold of 0.88, and SpliceAI shows a maximum delta score of 0.00, which is below the PP3 threshold of 0.38. These computational results do not support PP3. Details ▾Hide ▴
Rule
RUNX1 VCEP PP3
Evidence considered
  • REVEL score 0.245.
  • SpliceAI max delta score 0.00.
  • RUNX1 VCEP PP3 requires REVEL >= 0.88 or SpliceAI >= 0.38 for missense variants.
Sources
cspec ↗revelspliceai ↗
BA1 This variant is absent from gnomAD, with 0/1565090 alleles observed in gnomAD v4.1. The observed frequency is below the RUNX1 VCEP BA1 threshold of 0.0015, so BA1 is not met. Details ▾Hide ▴
Rule
RUNX1 VCEP BA1
Evidence considered
  • gnomAD v2.1: absent.
  • gnomAD v4.1: 0/1565090 alleles
  • AF 0.0.
  • RUNX1 VCEP BA1 threshold is >= 0.0015.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant is absent from gnomAD, with 0/1565090 alleles observed in gnomAD v4.1. The observed frequency is below the RUNX1 VCEP BS1 range of 0.00015 to 0.0015, so BS1 is not met. Details ▾Hide ▴
Rule
RUNX1 VCEP BS1
Evidence considered
  • gnomAD v2.1: absent.
  • gnomAD v4.1: 0/1565090 alleles
  • AF 0.0.
  • RUNX1 VCEP BS1 requires frequency between 0.00015 and 0.0015.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 10 · no assessment recorded

PS1 No previously established pathogenic or likely pathogenic variant with the same amino acid change was identified in the reviewed ClinVar summary or RUNX1 VCEP pilot materials, so PS1 cannot be applied from the available evidence. Details ▾Hide ▴
Rule
RUNX1 VCEP PS1
Evidence considered
  • RUNX1 VCEP PS1 requires the same amino acid change as a previously established pathogenic or likely pathogenic variant.
  • No matching precedent was identified in reviewed ClinVar summary or pilot material.
Still missing
  • Direct evidence of the same amino acid change previously established as pathogenic or likely pathogenic.
Sources
cspec ↗clinvar ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results
PS2 No confirmed de novo occurrence with documented maternity and paternity confirmation was identified, so PS2 cannot be applied. Details ▾Hide ▴
Rule
RUNX1 VCEP PS2
Evidence considered
  • RUNX1 VCEP PS2 requires confirmed de novo evidence.
  • Available ClinVar summary does not document a confirmed de novo occurrence.
Still missing
  • Proband-level report with confirmed maternity and paternity.
Sources
cspec ↗clinvar ↗
PS3 No well-established functional study showing abnormal RUNX1 function for this specific variant was identified, so PS3 cannot be assessed. Details ▾Hide ▴
Rule
RUNX1 VCEP PS3
Evidence considered
  • RUNX1 VCEP PS3 requires variant-specific abnormal functional evidence.
  • OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
  • Variant-specific validated functional studies showing altered transactivation and/or abnormal results in secondary assays.
Sources
cspec ↗oncokb ↗
PS4 This variant is reported in ClinVar, but no proband-level evidence was identified showing 1 or more affected individuals meeting RUNX1 VCEP phenotypic criteria. Available evidence is insufficient to assess PS4. Details ▾Hide ▴
Rule
RUNX1 VCEP PS4
Evidence considered
  • RUNX1 VCEP PS4 requires at least 1 qualifying proband for PS4_Supporting.
  • ClinVar shows an expert panel VUS classification but no qualifying proband count in the reviewed summary.
Still missing
  • Independent proband counts with RUNX1-specific phenotypic qualification.
Sources
cspec ↗clinvar ↗
PM5 No previously established pathogenic or likely pathogenic missense variant at this amino acid residue was identified in the reviewed evidence, so PM5 cannot be applied from the available materials. Details ▾Hide ▴
Rule
RUNX1 VCEP PM5
Evidence considered
  • RUNX1 VCEP PM5 requires a different pathogenic or likely pathogenic missense variant at the same residue and no predicted splice impact.
  • SpliceAI max delta score is 0.00.
  • No qualifying same-residue precedent was identified in the reviewed sources.
Still missing
  • Residue-level evidence showing a different pathogenic or likely pathogenic missense change at the same amino acid position.
Sources
cspec ↗clinvar ↗vcep_myeloid_malignancy_vcep_runx1_pilot_resultsspliceai ↗
PM6 No assumed de novo occurrences without parentage confirmation were identified, so PM6 cannot be assessed. Details ▾Hide ▴
Rule
RUNX1 VCEP PM6
Evidence considered
  • RUNX1 VCEP PM6 requires 2 to 3 assumed de novo occurrences for Supporting or at least 4 for Moderate.
  • Available ClinVar summary does not document assumed de novo occurrences.
Still missing
  • Case-level evidence describing assumed de novo occurrence in a patient with a RUNX1-related phenotype.
Sources
cspec ↗clinvar ↗
PP1 No segregation data were identified to show that this variant tracks with RUNX1-related disease in affected relatives, so PP1 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
RUNX1 VCEP PP1
Evidence considered
  • RUNX1 VCEP PP1 requires 3 or more informative meioses.
  • Available ClinVar summary does not provide segregation evidence.
Still missing
  • Family-level segregation data with informative meioses.
Sources
cspec ↗clinvar ↗
BS3 No well-established functional study showing normal RUNX1 function for this specific variant was identified, so BS3 cannot be assessed. Details ▾Hide ▴
Rule
RUNX1 VCEP BS3
Evidence considered
  • RUNX1 VCEP BS3 requires normal transactivation
  • with a secondary assay for full BS3.
  • OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
  • Variant-specific validated functional studies demonstrating normal transactivation and
  • for BS3
  • supporting normal function in a secondary assay.
Sources
cspec ↗oncokb ↗
BS4 No non-segregation data with at least 2 informative meioses were identified, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
RUNX1 VCEP BS4
Evidence considered
  • RUNX1 VCEP BS4 requires at least 2 informative non-segregating meioses.
  • No such pedigree data were identified.
Still missing
  • Family data showing lack of segregation in at least 2 informative meioses.
Sources
cspec ↗clinvar ↗
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. Details ▾Hide ▴
Rule
RUNX1 VCEP BP2
Evidence considered
  • RUNX1 VCEP BP2 follows ACMG phase-based requirements.
  • No phase information was identified in the reviewed evidence.
Still missing
  • Phase data with a known pathogenic variant.
Sources
cspec ↗clinvar ↗
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/ARUNX1 VCEP guidance does not allow use of PM3. Details ▾Hide ▴
Rule
RUNX1 VCEP PM3 not applicable
Evidence considered
  • RUNX1 VCEP marks PM3 as not applicable.
Sources
cspec ↗
PM4 N/APM4 in the RUNX1 specification applies to in-frame insertions or deletions and stop-loss variants. This is a missense substitution, so PM4 is not applicable. Details ▾Hide ▴
Rule
RUNX1 VCEP PM4
Evidence considered
  • RUNX1 VCEP PM4 is limited to in-frame indels and stop-loss variants.
Sources
cspec ↗
PP2 N/ARUNX1 VCEP guidance does not allow use of PP2. Details ▾Hide ▴
Rule
RUNX1 VCEP PP2 not applicable
Evidence considered
  • RUNX1 VCEP marks PP2 as not applicable.
Sources
cspec ↗
PP4 N/ARUNX1 VCEP guidance states that PP4 is not applicable because the RUNX1-related phenotype is not sufficiently specific to support this criterion. Details ▾Hide ▴
Rule
RUNX1 VCEP PP4 not applicable
Evidence considered
  • RUNX1 VCEP marks PP4 as not applicable.
Sources
cspec ↗
PP5 N/ARUNX1 VCEP guidance does not allow use of PP5. Details ▾Hide ▴
Rule
RUNX1 VCEP PP5 not applicable
Evidence considered
  • RUNX1 VCEP marks PP5 as not applicable.
Sources
cspec ↗
BS2 N/ARUNX1 VCEP guidance does not allow use of BS2. Details ▾Hide ▴
Rule
RUNX1 VCEP BS2 not applicable
Evidence considered
  • RUNX1 VCEP marks BS2 as not applicable.
Sources
cspec ↗
BP1 N/ARUNX1 VCEP guidance does not allow use of BP1. Details ▾Hide ▴
Rule
RUNX1 VCEP BP1 not applicable
Evidence considered
  • RUNX1 VCEP marks BP1 as not applicable.
Sources
cspec ↗
BP3 N/ARUNX1 VCEP guidance does not allow use of BP3. Details ▾Hide ▴
Rule
RUNX1 VCEP BP3 not applicable
Evidence considered
  • RUNX1 VCEP marks BP3 as not applicable.
Sources
cspec ↗
BP5 N/ARUNX1 VCEP guidance does not allow use of BP5. Details ▾Hide ▴
Rule
RUNX1 VCEP BP5 not applicable
Evidence considered
  • RUNX1 VCEP marks BP5 as not applicable.
Sources
cspec ↗
BP6 N/ARUNX1 VCEP guidance does not allow use of BP6. Details ▾Hide ▴
Rule
RUNX1 VCEP BP6 not applicable
Evidence considered
  • RUNX1 VCEP marks BP6 as not applicable.
Sources
cspec ↗
BP7 N/ABP7 is limited to synonymous and certain intronic variants. This is a missense variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
RUNX1 VCEP BP7
Evidence considered
  • RUNX1 VCEP BP7 applies only to synonymous and specified intronic variants.
Sources
cspec ↗

Identifiers

Gene
RUNX1
Transcript
NM_001001890.2
Coding (HGVS c.)
NM_001001890.2:c.1094A>C
Protein (HGVS p.)
NP_001001890.1:p.(Gln365Pro)
GRCh38
chr21:34792403 T>G
GRCh37
chr21:36164700 T>G

Gene diagram

Every interpreted variant in RUNX1, mapped onto the exon structure of NM_001001890.2. Select a row to find it on the plot.

RUNX1NM_001001890.2
Fetching transcript structure from UCSC…
gnomAD v4.1 0 / 1,565,090 alleles AF 0 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,565,090 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1565090 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73964 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingFor this missense variant, REVEL is 0.245, which is below the RUNX1 VCEP BP4 threshold of 0.50, and SpliceAI shows a maximum delta score of 0.00, which is at or below the BP4 threshold of 0.20. BayesDel is also negative at -0.122289, which does not support a damaging effect. These computational results support BP4. Details ▾Hide ▴
Rule
RUNX1 VCEP BP4
Evidence considered
  • REVEL score 0.245.
  • SpliceAI max delta score 0.00.
  • BayesDel score -0.122289.
  • RUNX1 VCEP BP4 requires REVEL < 0.50 and SpliceAI <= 0.20 for missense variants.
Sources
cspec ↗revelspliceai ↗bayesdel
PP3 For this missense variant, REVEL is 0.245, which is below the RUNX1 VCEP PP3 threshold of 0.88, and SpliceAI shows a maximum delta score of 0.00, which is below the PP3 threshold of 0.38. These computational results do not support PP3. Details ▾Hide ▴
Rule
RUNX1 VCEP PP3
Evidence considered
  • REVEL score 0.245.
  • SpliceAI max delta score 0.00.
  • RUNX1 VCEP PP3 requires REVEL >= 0.88 or SpliceAI >= 0.38 for missense variants.
Sources
cspec ↗revelspliceai ↗
BP7 N/ABP7 is limited to synonymous and certain intronic variants. This is a missense variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
RUNX1 VCEP BP7
Evidence considered
  • RUNX1 VCEP BP7 applies only to synonymous and specified intronic variants.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.245. BayesDel score = -0.122289.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 0 / 1,565,090 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1565090 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73964 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

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).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.245. BayesDel score = -0.122289.

Functional

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

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.