KMT2A c.3086del, p.Lys1029ArgfsTer65
NM_005933.3:c.3086del
COSMIC ID: COSM6697145
Pathogenic
This frameshift variant in KMT2A results in premature truncation and loss of methyltransferase function. It is absent from controls and supported by functional studies. The application of PVS1 (Very Strong), PS3 (Strong), and PM2 (Moderate) criteria meets ACMG guidelines for a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
Genetic Information
Gene & Transcript Details
Gene
KMT2A
Transcript
NM_005933.4
Total Exons
36
Strand
Forward (+)
Reference Sequence
NC_000011.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_005933.2 | Alternative | 36 exons | Forward |
| NM_005933.3 | Alternative | 36 exons | Forward |
Variant Details
HGVS Notation
NM_005933.3:c.3086del
Protein Change
K1029Rfs*65
Location
Exon 3
(Exon 3 of 36)
5'Exon Structure (36 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1029 in gene KMT2A
Alternate Identifiers
COSM6697145
Variant interpretation based on transcript NM_005933.4
Genome Browser
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HGVS InputNM_005933:c.3086del
Active Tracks
ConservationRefSeqClinVargnomAD
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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).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
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 1029 in gene KMT2A
Functional Summary
The KMT2A K1029Rfs*65 variant is a truncating mutation in the KMT2A gene, which is a tumor suppressor. Functional evidence indicates that truncating mutations in KMT2A typically result in proteins lacking methyltransferase activity. Although these mutations alone do not spontaneously induce tumor formation in mice, they may contribute to the dysregulation of genes involved in tumorigenesis.
Database Previews
OncoKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Very Strong)
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 deletion in a LoF gene)". The evidence for this variant shows: c.3086delA results in a frameshift leading to a premature stop codon (K1029Rfs*65) in KMT2A, a gene where LoF is established as a disease mechanism. Therefore, this criterion is applied at Very Strong strength because this is a truncating variant expected to result in loss of function.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: there is no report of a different nucleotide change resulting in the same amino acid alteration. Therefore, this criterion is not applied because the variant does not match a known pathogenic 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: parental testing data are not available. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3
PS3 (Strong)
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: functional studies indicate that truncating mutations in KMT2A abolish methyltransferase activity and contribute to dysregulation of genes involved in tumorigenesis. Therefore, this criterion is applied at Strong strength because well-established in vitro/in vivo studies support a damaging effect.
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 prevalence data are available. Therefore, this criterion is not applied due to absence of statistical association data.
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: exon/domain structure and hotspot data are not defined. Therefore, this criterion is not applied due to lack of localization information.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: absent from population databases including gnomAD (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is not observed in 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: phasing and zygosity information relative to another pathogenic variant are not available. Therefore, this criterion is not applied due to lack of trans configuration data.
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 frameshift leading to truncation rather than an in-frame change. Therefore, this criterion is not applied because the variant is not an in-frame indel or stop-loss.
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: it is not a missense change. Therefore, this criterion is not applied.
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 data on de novo status are available. Therefore, this criterion is not applied.
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 segregation data are available. Therefore, this criterion is not applied due to lack of family studies.
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: it is a frameshift variant, not missense. Therefore, this criterion is not applied.
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/gene product (e.g., conservation, splicing impact)". The evidence for this variant shows: in silico splicing prediction (SpliceAI max 0.07) indicates minimal impact and no other deleterious computational evidence. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no detailed phenotype/family history provided. Therefore, this criterion is not applied.
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: not found in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: allele frequency is 0% in gnomAD, not high. Therefore, this criterion is not applied.
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: allele frequency is 0%, below disease threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: no observation in healthy individuals. Therefore, this criterion is not applied.
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: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
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: segregation data are not available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: it is a frameshift variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no data on cis/trans configuration. Therefore, this criterion is not applied.
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 known function". The evidence for this variant shows: it is a frameshift, not an in-frame event in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: computational evidence is insufficient to suggest no impact because the variant truncates the protein. Therefore, this criterion is not applied.
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 alternate molecular basis reported. Therefore, this criterion is not applied.
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: not reported as benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is not synonymous. Therefore, this criterion is not applied.