KMT2A c.3802G>A, p.Glu1268Lys

NM_005933.3:c.3802G>A
Variant of Uncertain Significance (VUS)
NM_005933.3:c.3802G>A (p.E1268K) in KMT2A is classified as a Variant of Uncertain Significance (VUS). It is absent from population databases (PM2, Moderate) but computational evidence leans benign (BP4, Supporting). No additional pathogenic or benign evidence is available to shift classification.
ACMG/AMP Criteria Applied
PM2 BP4

Genetic Information

Gene & Transcript Details
Gene
KMT2A
Transcript
NM_005933.4
Total Exons
36
Strand
Forward (+)
Reference Sequence
NC_000011.9
Alternative Transcripts
IDStatusDetails
NM_005933.2 Alternative 36 exons | Forward
NM_005933.3 Alternative 36 exons | Forward
Variant Details
HGVS Notation
NM_005933.3:c.3802G>A
Protein Change
E1268K
Location
Exon 7 (Exon 7 of 36)
7
5'Exon Structure (36 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1268 in gene KMT2A
Variant interpretation based on transcript NM_005933.4

Genome Browser

UCSC Genome Browser hg19/GRCh37
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HGVS InputNM_005933:c.3802G>A
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Clinical Data

Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
ClinVar 2025-06-02T10:32:23.735377
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
COSMIC
COSMIC ID
Unknown
Recurrence
0 occurrences
PM1 Criteria
Not Applied
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Functional Impact

Functional Domain
Hotspot Status
Not a hotspot
Domain Summary

This variant is not located in a mutational hotspot or critical domain (0 mutations).

Related Variants in This Domain
No evidence of other pathogenic variants at position 1268 in gene KMT2A
Functional Studies & Therapeutic Relevance
Functional Summary
The KMT2A E1268K variant has not been functionally characterized.
Database Previews
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Computational Analysis

Pathogenicity Predictions
REVEL Score
0.474
0.474
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
metasvm: Dmetalr: D
Benign:
CADD: 3.51polyphen_prediction: benignprimateai: T
Neutral: Show all
SpliceAI Scores Window: ±500bp
Effect TypeScorePosition
-Acceptor Loss
0.0
-197 bp
-Donor Loss
0.0
398 bp
+Acceptor Gain
0.0
67 bp
+Donor Gain
0.0
-27 bp
High impact (≥0.5)
Medium impact (0.2-0.49)
Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multi‐exon deletion in a LoF gene)'. The evidence for this variant shows: 'This variant is a missense change (E1268K) and not predicted to create a null allele, and LoF is not an established mechanism of disease for KMT2A.' Therefore, this criterion is not applied at Not Applied strength because the variant is not a null variant and LoF is not a known mechanism for KMT2A.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change'. The evidence for this variant shows: 'No previously established pathogenic variant results in the same E1268K amino acid change.' Therefore, this criterion is not applied at Not Applied strength because there is no known pathogenic variant with the same amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows: 'No information on de novo occurrence or parental testing is available.' Therefore, this criterion is not applied at Not Applied strength because de novo status has not been confirmed.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: 'Well‐established functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows: 'No functional studies have been performed on KMT2A E1268K.' Therefore, this criterion is not applied at Not Applied strength because functional impact data are lacking.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: 'No case‐control or cohort data demonstrating increased prevalence in affected individuals.' Therefore, this criterion is not applied at Not Applied strength due to absence of case‐control evidence.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well‐established functional domain without benign variation'. The evidence for this variant shows: 'E1268K is not reported within a recognized mutational hotspot or critical functional domain in KMT2A.' Therefore, this criterion is not applied at Not Applied strength because the variant does not reside in a known hotspot or critical domain.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive) (Table 6) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium'. The evidence for this variant shows: 'Variant not found in population databases (gnomAD), MAF = 0%'. Therefore, this criterion is applied at Moderate strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant for recessive disorders'. The evidence for this variant shows: 'No data on trans phase with a pathogenic variant are available.' Therefore, this criterion is not applied at Not Applied strength because trans configuration with a pathogenic allele is not demonstrated.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in‐frame deletions/insertions or stop‐loss variants'. The evidence for this variant shows: 'This is a missense substitution with no change in protein length.' Therefore, this criterion is not applied at Not Applied strength because no protein length change occurs.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence for this variant shows: 'No other missense changes at residue E1268 have been reported as pathogenic.' Therefore, this criterion is not applied at Not Applied strength because there is no precedent pathogenic change at this residue.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: 'No de novo or parental testing data exist.' Therefore, this criterion is not applied at Not Applied strength because de novo occurrence is unconfirmed.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Co‐segregation with disease in multiple affected family members'. The evidence for this variant shows: 'No family segregation data available.' Therefore, this criterion is not applied at Not Applied strength because segregation evidence is lacking.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant shows: 'KMT2A disease mechanism is not predominantly driven by missense variation and benign missense variation rate is unclear.' Therefore, this criterion is not applied at Not Applied strength because the gene does not meet PP2 characteristics.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product'. The evidence for this variant shows: 'In silico predictions are mixed, with some tools predicting deleterious (MetaSVM=D, MetaLR=D) and others predicting benign (CADD=3.51, PolyPhen benign, SpliceAI no impact). Overall computational evidence leans benign.' Therefore, this criterion is not applied at Not Applied strength because computational evidence does not consistently support a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history is highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: 'No phenotype or clinical information provided.' Therefore, this criterion is not applied at Not Applied strength because phenotype specificity cannot be assessed.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence for this variant shows: 'No reputable source has reported this variant as pathogenic.' Therefore, this criterion is not applied at Not Applied strength because no external pathogenic assertion exists.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder'. The evidence for this variant shows: 'MAF = 0% in population databases.' Therefore, this criterion is not applied at Not Applied strength because allele frequency is not above the BA1 threshold.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: 'MAF = 0% in population databases.' Therefore, this criterion is not applied at Not Applied strength because allele frequency does not exceed disease‐specific thresholds.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a dominant (with full penetrance expected at an early age), X‐linked or mitochondrial disorder with full penetrance expected at an early age'. The evidence for this variant shows: 'No observations in healthy individuals are reported.' Therefore, this criterion is not applied at Not Applied strength because healthy adult occurrence is not documented.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Well‐established functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows: 'No functional studies are available to demonstrate lack of effect.' Therefore, this criterion is not applied at Not Applied strength because functional evidence is absent.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. The evidence for this variant shows: 'No family segregation data are available.' Therefore, this criterion is not applied at Not Applied strength because lack of segregation cannot be evaluated.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only loss of function causes disease'. The evidence for this variant shows: 'KMT2A disease mechanisms include structural rearrangements and haploinsufficiency, not exclusively LoF.' Therefore, this criterion is not applied at Not Applied strength because missense changes are not automatically benign in this gene.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant'. The evidence for this variant shows: 'No information on cis/trans configuration with pathogenic variants.' Therefore, this criterion is not applied at Not Applied strength because phase data are lacking.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In‐frame deletions/insertions in a repetitive region without a known function'. The evidence for this variant shows: 'This is a missense substitution, not an in‐frame indel.' Therefore, this criterion is not applied at Not Applied strength because the variant type does not match BP3.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)'. The evidence for this variant shows: 'In silico predictions are overall benign: CADD=3.51, PolyPhen benign, SpliceAI no impact, REVEL=0.47, despite mixed results from MetaSVM and MetaLR.' Therefore, this criterion is applied at Supporting strength because multiple computational tools predict no damaging effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: 'No reports of this variant in cases with an alternate genetic cause.' Therefore, this criterion is not applied at Not Applied strength because no alternate molecular basis is documented.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows: 'No reputable source has reported it as benign.' Therefore, this criterion is not applied at Not Applied strength because no external benign assertion exists.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous (silent) variant with no predicted impact on splicing'. The evidence for this variant shows: 'This is a missense variant, not synonymous.' Therefore, this criterion is not applied at Not Applied strength because the variant is not synonymous.