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RUNX1c.1036T>GUncertain significance
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Variant interpretation report

RUNX1 c.1036T>G, p.(Ser346Ala)

NM_001001890.2:c.1036T>G NP_001001890.1:p.(Ser346Ala) 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 gnomAD v4.1, which is below the RUNX1 PM2_Supporting threshold of <=0.00005.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Computational evidence supports a benign interpretation because the REVEL score is 0.262, below the RUNX1 BP4 threshold of <0.50, and the SpliceAI max delta score is 0.00, within the <=0.20 threshold for no predicted splice impact. The BayesDel score of -0.17459 is also consistent with low predicted deleteriousness.

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 · 12 not met · 2 not assessed · 12 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.1036T>G (p.(Ser346Ala)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as uncertain significance, including an expert panel submission from the ClinGen Myeloid Malignancy Variant Curation Expert Panel.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2_Supporting under the RUNX1 threshold of <=0.00005.

Computational evidence argues against a damaging effect because REVEL is 0.262, below the RUNX1 PP3 threshold and within the BP4 range, SpliceAI shows no predicted splice impact with a max delta score of 0.00, and BayesDel is -0.17459.

Met · 2

PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the RUNX1 PM2_Supporting threshold of <=0.00005. Details ▾Hide ▴
Rule
RUNX1 PM2_Supporting: minor allele frequency <=0.00005.
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BP4 SupportingComputational evidence supports a benign interpretation because the REVEL score is 0.262, below the RUNX1 BP4 threshold of <0.50, and the SpliceAI max delta score is 0.00, within the <=0.20 threshold for no predicted splice impact. The BayesDel score of -0.17459 is also consistent with low predicted deleteriousness. Details ▾Hide ▴
Rule
RUNX1 BP4 for missense variants requires REVEL <0.50 and SpliceAI <=0.20.
Evidence considered
  • REVEL score 0.262.
  • SpliceAI max delta score 0.00.
  • BayesDel score -0.17459.
Sources
revelspliceai ↗bayesdelcspec ↗

Not met · 12 · evaluated, threshold not reached

PS1 No evidence was identified that this variant causes the same amino acid change as a previously established pathogenic or likely pathogenic RUNX1 variant. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic or likely pathogenic variant.
Evidence considered
  • ClinVar lists this variant as uncertain significance.
  • No matching pathogenic/likely pathogenic same-amino-acid precedent was found in the reviewed RUNX1 pilot results file.
Still missing
  • No confirmed pathogenic or likely pathogenic alternate nucleotide change producing this same amino acid substitution was identified.
Sources
clinvar ↗vcep_myeloid_malignancy_vcep_runx1_pilot_resultscspec ↗
PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant. Details ▾Hide ▴
Rule
PS2_Supporting requires 1 proven de novo case; PS2_Moderate requires >=2 proven de novo cases in the RUNX1 framework.
Evidence considered
  • ClinVar did not provide de novo evidence for this variant.
Still missing
  • No case-level parental testing data were identified.
Sources
clinvar ↗cspec ↗
PS4 No affected proband count or enrichment data were identified for this variant, so case-level overrepresentation has not been established. Details ▾Hide ▴
Rule
RUNX1 PS4 requires >=1 proband meeting phenotype criteria, with strength based on case count.
Evidence considered
  • ClinVar shows limited reporting.
  • The variant is absent from gnomAD
  • but no affected-case enrichment data were identified.
Still missing
  • No unrelated proband series or odds-ratio data were identified for this variant.
Sources
clinvar ↗gnomad_v2 ↗gnomad_v4 ↗cspec ↗
PM1 This missense change affects Ser346, which is outside the RUNX1 Runt homology domain residues used by the RUNX1 specification for PM1, and no hotspot evidence supports this site as a critical region. Details ▾Hide ▴
Rule
PM1 applies to specified RUNX1 RHD residues; stronger evidence is limited to designated hotspot residues.
Evidence considered
  • RUNX1 PM1 is restricted to residues 89-204 within the Runt homology domain.
  • Cancer Hotspots did not identify a statistically significant hotspot for this variant.
Still missing
  • No residue-specific hotspot evidence supporting codon 346 as a critical region was identified.
Sources
cspec ↗hotspots ↗
PM5 No evidence was identified that a different pathogenic or likely pathogenic missense variant has been established at this same residue, so PM5 is not supported. Details ▾Hide ▴
Rule
RUNX1 PM5 requires a different pathogenic/likely pathogenic missense change at the same amino acid residue.
Evidence considered
  • No same-residue pathogenic or likely pathogenic precedent was found in the reviewed sources.
  • SpliceAI does not suggest a splicing effect that would otherwise complicate PM5 assessment.
Still missing
  • No confirmed pathogenic or likely pathogenic alternate missense change at this codon was identified.
Sources
clinvar ↗vcep_myeloid_malignancy_vcep_runx1_pilot_resultscspec ↗spliceai ↗
PM6 No assumed de novo occurrences without full parental confirmation were identified for this variant. Details ▾Hide ▴
Rule
RUNX1 PM6_Supporting requires 2-3 assumed de novo cases; PM6 requires >=4 assumed de novo cases.
Evidence considered
  • ClinVar did not provide de novo case-level evidence.
Still missing
  • No case reports with limited but suggestive de novo evidence were identified.
Sources
clinvar ↗cspec ↗
PP1 No segregation data were identified for this variant, so cosegregation with RUNX1-related disease has not been established. Details ▾Hide ▴
Rule
RUNX1 PP1 requires 3-4 informative meioses, with higher strengths for additional meioses.
Evidence considered
  • No family segregation evidence was available in the reviewed sources.
Still missing
  • No informative meioses were identified.
Sources
clinvar ↗cspec ↗
PP3 Available computational evidence does not support a damaging effect under the RUNX1 PP3 rule because REVEL is 0.262, below the >=0.88 threshold, and SpliceAI is 0.00, below the >=0.38 threshold. Details ▾Hide ▴
Rule
RUNX1 PP3 for missense variants requires REVEL >=0.88 or SpliceAI >=0.38.
Evidence considered
  • REVEL score 0.262.
  • SpliceAI max delta score 0.00.
Sources
revelspliceai ↗cspec ↗
BA1 This variant is absent from population databases and does not meet the RUNX1 BA1 threshold of >=0.0015 in a general population dataset. Details ▾Hide ▴
Rule
RUNX1 BA1 requires minor allele frequency >=0.0015.
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BS1 This variant is absent from population databases and does not meet the RUNX1 BS1 range of 0.00015 to 0.0015. Details ▾Hide ▴
Rule
RUNX1 BS1 requires minor allele frequency between 0.00015 and 0.0015.
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BS4 No lack-of-segregation data were identified for this variant, so BS4 is not supported. Details ▾Hide ▴
Rule
RUNX1 BS4 requires observation in >=2 informative non-segregation meioses.
Evidence considered
  • No family non-segregation evidence was available in the reviewed sources.
Still missing
  • No informative non-segregation meioses were identified.
Sources
clinvar ↗cspec ↗
BP2 No evidence was identified that this variant is observed in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant. Details ▾Hide ▴
Rule
Observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant.
Evidence considered
  • No cis/trans observations were reported in the reviewed sources.
Still missing
  • No phase data were identified.
Sources
clinvar ↗cspec ↗

Not assessed · 2 · no assessment recorded

PS3 No variant-specific functional study demonstrating abnormal RUNX1 function was identified, so PS3 could not be evaluated from the available evidence. Details ▾Hide ▴
Rule
RUNX1 PS3 requires abnormal transactivation and/or qualifying secondary assay evidence.
Evidence considered
  • OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
  • No transactivation assay or secondary functional assay result specific to p.(Ser346Ala) was identified.
Sources
oncokb ↗cspec ↗
BS3 No variant-specific functional study showing normal RUNX1 activity was identified, so BS3 could not be evaluated from the available evidence. Details ▾Hide ▴
Rule
RUNX1 BS3 requires normal transactivation, with stronger evidence when supported by a secondary normal assay.
Evidence considered
  • OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
  • No transactivation assay demonstrating 80-115% of wild-type activity was identified.
  • No qualifying secondary assay showing normal function was identified.
Sources
oncokb ↗cspec ↗
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis missense variant does not create a nonsense, frameshift, or canonical +/-1,2 splice-site change, and available splice prediction does not indicate an RNA effect that would support a loss-of-function mechanism for PVS1. Details ▾Hide ▴
Rule
RUNX1 VCEP PVS1 framework; this variant type does not meet PVS1 conditions.
Evidence considered
  • RUNX1 is PVS1-eligible at the gene level
  • but this specific variant is a missense substitution outside the generic null-variant categories.
  • SpliceAI max delta score is 0.00.
Still missing
  • No variant-specific RNA study was identified.
Sources
pvs1_gene_contextpvs1_variant_assessmentcspec ↗spliceai ↗
PM3 N/APM3 is not applicable in the RUNX1 specification for this dominant disorder context. Details ▾Hide ▴
Rule
Not applicable per RUNX1 VCEP.
Evidence considered
  • RUNX1 VCEP marks PM3 as not applicable.
Sources
cspec ↗
PM4 N/APM4 is reserved for in-frame insertions/deletions affecting specified RUNX1 residues or for stop-loss variants, and this variant is a missense substitution. Details ▾Hide ▴
Rule
RUNX1 PM4 applies to qualifying in-frame indels or stop-loss variants.
Evidence considered
  • Variant type is missense
  • not in-frame indel or stop-loss.
Sources
cspec ↗
PP2 N/APP2 is not applicable in the RUNX1 specification. Details ▾Hide ▴
Rule
Not applicable per RUNX1 VCEP.
Evidence considered
  • RUNX1 VCEP marks PP2 as not applicable.
Sources
cspec ↗
PP4 N/APP4 is not applicable in the RUNX1 specification because the associated phenotype is not sufficiently specific for this criterion. Details ▾Hide ▴
Rule
Not applicable per RUNX1 VCEP.
Evidence considered
  • RUNX1 VCEP marks PP4 as not applicable.
Sources
cspec ↗
PP5 N/APP5 is not used in the RUNX1 specification. Details ▾Hide ▴
Rule
Not applicable per ClinGen SVI/VCEP recommendation.
Evidence considered
  • RUNX1 VCEP marks PP5 as not applicable.
Sources
cspec ↗
BS2 N/ABS2 is not applicable in the RUNX1 specification. Details ▾Hide ▴
Rule
Not applicable per RUNX1 VCEP.
Evidence considered
  • RUNX1 VCEP marks BS2 as not applicable.
Sources
cspec ↗
BP1 N/ABP1 is not applicable in the RUNX1 specification. Details ▾Hide ▴
Rule
Not applicable per RUNX1 VCEP.
Evidence considered
  • RUNX1 VCEP marks BP1 as not applicable.
Sources
cspec ↗
BP3 N/ABP3 is not applicable in the RUNX1 specification. Details ▾Hide ▴
Rule
Not applicable per RUNX1 VCEP.
Evidence considered
  • RUNX1 VCEP marks BP3 as not applicable.
Sources
cspec ↗
BP5 N/ABP5 is not applicable in the RUNX1 specification. Details ▾Hide ▴
Rule
Not applicable per RUNX1 VCEP.
Evidence considered
  • RUNX1 VCEP marks BP5 as not applicable.
Sources
cspec ↗
BP6 N/ABP6 is not applicable in the RUNX1 specification. Details ▾Hide ▴
Rule
Not applicable per RUNX1 VCEP.
Evidence considered
  • RUNX1 VCEP marks BP6 as not applicable.
Sources
cspec ↗
BP7 N/ABP7 is limited to qualifying synonymous or intronic variants, and this variant is missense. Details ▾Hide ▴
Rule
RUNX1 BP7 applies to qualifying synonymous or intronic variants with low splice impact.
Evidence considered
  • Variant type is missense
  • not synonymous or intronic.
Sources
cspec ↗

Identifiers

Gene
RUNX1
Transcript
NM_001001890.2
Coding (HGVS c.)
NM_001001890.2:c.1036T>G
Protein (HGVS p.)
NP_001001890.1:p.(Ser346Ala)
GRCh38
chr21:34792461 A>C
GRCh37
chr21:36164758 A>C

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 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingComputational evidence supports a benign interpretation because the REVEL score is 0.262, below the RUNX1 BP4 threshold of <0.50, and the SpliceAI max delta score is 0.00, within the <=0.20 threshold for no predicted splice impact. The BayesDel score of -0.17459 is also consistent with low predicted deleteriousness. Details ▾Hide ▴
Rule
RUNX1 BP4 for missense variants requires REVEL <0.50 and SpliceAI <=0.20.
Evidence considered
  • REVEL score 0.262.
  • SpliceAI max delta score 0.00.
  • BayesDel score -0.17459.
Sources
revelspliceai ↗bayesdelcspec ↗
PP3 Available computational evidence does not support a damaging effect under the RUNX1 PP3 rule because REVEL is 0.262, below the >=0.88 threshold, and SpliceAI is 0.00, below the >=0.38 threshold. Details ▾Hide ▴
Rule
RUNX1 PP3 for missense variants requires REVEL >=0.88 or SpliceAI >=0.38.
Evidence considered
  • REVEL score 0.262.
  • SpliceAI max delta score 0.00.
Sources
revelspliceai ↗cspec ↗
BP7 N/ABP7 is limited to qualifying synonymous or intronic variants, and this variant is missense. Details ▾Hide ▴
Rule
RUNX1 BP7 applies to qualifying synonymous or intronic variants with low splice impact.
Evidence considered
  • Variant type is missense
  • not synonymous or intronic.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.262. BayesDel score = -0.17459.

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 Captured gnomAD v4.1 source record 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

Absent from gnomAD v4.1.

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 = 0.262. BayesDel score = -0.17459.

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.