The RUNX1 NM_001001890.2:c.619A>G (p.(Thr207Ala)) variant has been reported in ClinVar and is currently classified there as uncertain significance, including an expert-panel submission from the ClinGen Myeloid Malignancy Variant Curation Expert Panel.1 This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1, with 2/1,612,820 alleles overall and grpmax FAF 2.8e-07, which supports PM2 at supporting strength under the RUNX1 VCEP threshold of 0.00005.2 Computational data do not support a splice effect, with SpliceAI max delta score 0.01, and the missense prediction is indeterminate under the RUNX1 VCEP computational rules because REVEL is 0.581, below the PP3 threshold of 0.88 and above the BP4 threshold of 0.50; BayesDel is 0.0617795.3
Final classification
VUS
PM2
RUNX1
c.619A>G
p.Thr207Ala
This variant
The RUNX1 NM_001001890.2:c.619A>G (p.(Thr207Ala)) variant has been reported in ClinVar and is currently classified there as uncertain significance, including an expert-panel submission from the ClinGen Myeloid Malignancy Variant Curation Expert Panel.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PM2 supporting (+1) = 1 points, which maps to VUS.
Classification rationale
PM2
VUS
RUNX1 c.619A>G
PM2
→
VUS
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 · 1 applied · 16 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 · 1
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1, with 2/1,612,820 alleles overall and grpmax FAF 2.8e-07. This is below the RUNX1 PM2_Supporting threshold of 0.00005 with more than 2,000 alleles evaluated.
RUNX1 VCEP PM2 thresholdgnomAD v2.1gnomAD v4.1 grpmax FAF
Assessed · not applied
· 8 not met · 8 not assessed
Pathogenic
PVS1
This is a missense substitution, p.(Thr207Ala), and does not fall into the RUNX1 loss-of-function variant categories used for PVS1.
PS1
No evidence was identified that this variant causes the same amino acid change as a previously established pathogenic or likely pathogenic RUNX1 variant.
PS2
No confirmed de novo occurrence with maternity and paternity testing was identified for this variant.
PS3
No published variant-specific functional study was identified showing altered RUNX1 transactivation or abnormal secondary assay results for this variant.
PS4
This variant is reported in ClinVar, but no proband count meeting RUNX1 phenotypic criteria was identified to support case enrichment under the RUNX1 PS4 rules.
PM1
This missense variant affects Thr207, which is outside the RUNX1 VCEP PM1-defined residues 89-204 in the Runt homology domain, and available hotspot review did not identify a statistically significant hotspot at this residue.
PM5
No evidence was identified for a different pathogenic or likely pathogenic missense change at this same amino acid residue, and SpliceAI does not suggest a splice effect that would alter the interpretation of a missense comparison.
PM6
No assumed de novo occurrence without confirmed parentage was identified for this variant.
PP1
No segregation data were identified for this variant in affected relatives.
PP3
Computational evidence does not meet the RUNX1 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 published variant-specific functional study was identified showing normal RUNX1 transactivation or normal secondary assay results for this variant.
BS4
No non-segregation data were identified for this variant.
BP2
No evidence was identified that this variant occurs in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant.
BP4
Computational evidence does not meet the RUNX1 BP4 threshold.
N/A · 11
PM3 · PM4 · PP2 · PP4 · PP5 · BS2 · BP1 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.24006e-06; MAF= 0.00012%, 2/1612820 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69497e-06; MAF= 0.00017%, 2/1179962 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00012%
· 2 / 1,612,820
0 hom · FAF 2.8e-05%
0 hom · FAF 2.8e-05%
European (non-Finnish) 2 / 1,179,962 |
0.00017% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) 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 = 0.01). REVEL score = 0.581. BayesDel score = 0.0617795.
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
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.
Sources & reference links