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LYFE SCIENCES
Project: HERA
NM_005933.3:c.8956G>A
p.Glu2986Lys  ·  KMT2A
ACMG/AMP
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Legacy Engine
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Classification rationale
1

The KMT2A c.8956G>A (p.Glu2986Lys) variant has been reported in ClinVar with benign and likely benign single-submitter classifications.

clinvar ↗
2

This variant is present in population databases, with gnomAD v2.1 AF 0.02406% (68/282608) and gnomAD v4.1 AF 0.02757% (445/1614106), including 1 homozygote in gnomAD v4.1.

gnomad_v2 ↗ gnomad_v4 ↗
3

Available hotspot review did not identify this residue within a statistically significant mutational hotspot.

hotspots ↗
4

In silico results are inconclusive overall: SpliceAI predicts no significant splice effect (max delta score 0.00), while REVEL 0.527 and BayesDel 0.269249 do not provide a concordant benign or pathogenic signal.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 0.000240616; MAF= 0.02406%, 68/282608 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000434223; MAF= 0.04342%, 56/128966 alleles, homozygotes = 0); grpmax FAF= 0.00035778.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 0.000275694; MAF= 0.02757%, 445/1614106 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00034915; MAF= 0.03491%, 412/1180010 alleles, homozygotes = 1); grpmax FAF= 0.00032126.
gnomAD CanadaThis variant is present in gnomAD-Canada v1.0 (AF= 0.000108613; MAF= 0.01086%, 2/18414 alleles, homozygotes = 0) and has highest observed frequency in the nfe population (AF= 0.000170416; grpmax FAF95= 3.01e-05).
gnomAD v2 ↗ gnomAD v4 ↗ gnomAD 🇨🇦 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Benign (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 444273)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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. KMT2A, a histone methyltransferase, is altered by mutation or deletion in various solid tumors, and by chromosomal rearrangement in various hematologi
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.527. BayesDel score = 0.269249.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueE2986
Hotspots ↗