KMT2A c.3180G>T, p.Glu1060Asp
NM_005933.3:c.3180G>T
COSMIC ID: COSM282812
Variant of Uncertain Significance (VUS)
KMT2A c.3180G>T (p.E1060D) is classified as a Variant of Uncertain Significance. It meets PM2 (Moderate) due to its extreme rarity in population databases and BP4 (Supporting) based on computational evidence suggesting no impact. No additional pathogenic or benign criteria are met, and critical data such as functional studies, segregation, de novo status, and case-control evidence are lacking.
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
| 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.3180G>T
Protein Change
E1060D
Location
Exon 4
(Exon 4 of 36)
5'Exon Structure (36 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1060 in gene KMT2A
Alternate Identifiers
COSM282812
Variant interpretation based on transcript NM_005933.4
Genome Browser
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HGVS InputNM_005933:c.3180G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000796%
Very Rare
Highest in Population
South Asian
0.00327%
Rare
Global: 0.000796%
South Asian: 0.00327%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251210Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000796%, 2/251210 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.00327%, 1/30566 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories).
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 1060 in gene KMT2A
Functional Summary
The KMT2A E1060D variant has not been functionally characterized, and its effect on KMT2A protein function is unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.336
0.336
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:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 4.59
Neutral: Show all
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 deletion in a LoF gene)". The evidence for this variant shows: NM_005933.3:c.3180G>T (p.E1060D) is a missense change, not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant is not a null variant.
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: there is no report of a pathogenic variant causing the same E1060D amino acid change. Therefore, this criterion is not applied at Not Applied strength because no known pathogenic variant shares this 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 de novo status or parental testing data are available. Therefore, this criterion is not applied at Not Applied strength because there is no confirmed de novo occurrence.
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 for KMT2A p.E1060D. Therefore, this criterion is not applied at Not Applied strength because functional 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 affected individual data are available. Therefore, this criterion is not applied at Not Applied strength because there is no statistical enrichment in cases.
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: residue E1060 is not known to reside in a mutational hotspot or critical functional domain. Therefore, this criterion is not applied at Not Applied strength because the variant is not in a recognized hotspot or domain.
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: the variant is extremely rare in population databases (gnomAD MAF = 0.000796%). Therefore, this criterion is applied at Moderate strength because the variant is absent or at an extremely low frequency 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: no data on trans configuration with a pathogenic allele are available. Therefore, this criterion is not applied at Not Applied strength because trans data are lacking.
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: p.E1060D is a missense substitution without change in protein length. Therefore, this criterion is not applied at Not Applied strength because there is no alteration in protein length.
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 different pathogenic missense variant at residue 1060 has been reported. Therefore, this criterion is not applied at Not Applied strength because no pathogenic change at this residue is known.
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 assumed de novo data are available. Therefore, this criterion is not applied at Not Applied strength because parental status has not been assessed.
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 are provided. Therefore, this criterion is not applied at Not Applied strength because co-segregation data are 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: insufficient data to conclude that missense is the predominant mechanism for KMT2A or that benign missense variation is low. Therefore, this criterion is not applied at Not Applied strength because the gene-specific context is unclear.
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 predictions are mixed, REVEL score is low (0.34), CADD score is 4.59, and SpliceAI predicts no impact on splicing. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not consistently predict deleteriousness.
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 phenotype or clinical details are provided. Therefore, this criterion is not applied at Not Applied strength because phenotype-specific data are unavailable.
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: ClinVar classifies this variant as Uncertain Significance, not pathogenic. Therefore, this criterion is not applied at Not Applied strength because there is no reputable report of pathogenicity.
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: MAF is 0.000796%, which is well below the BA1 threshold. Therefore, this criterion is not applied at Not Applied strength because allele frequency is not high enough.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder". The evidence for this variant shows: MAF is extremely low and not greater than disease-specific thresholds. Therefore, this criterion is not applied at Not Applied strength because the frequency is consistent with a rare variant.
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 data on observation in healthy individuals. Therefore, this criterion is not applied at Not Applied strength because healthy adult data are unavailable.
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 assays have been performed. Therefore, this criterion is not applied at Not Applied strength because functional study data are lacking.
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 segregation data are provided. Therefore, this criterion is not applied at Not Applied strength because segregation evidence is unavailable.
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: the mechanism of KMT2A-related disease is not exclusively loss-of-function, and no data support a benign missense mechanism. Therefore, this criterion is not applied at Not Applied strength.
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 phase data exist. Therefore, this criterion is not applied at Not Applied strength because cis/trans configuration is unknown.
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: this is a missense substitution, not an in-frame indel in a repetitive region. Therefore, this criterion is not applied at Not Applied strength.
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". The evidence for this variant shows: in silico predictors are mixed overall, with a low CADD score (4.59), REVEL 0.34, and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Supporting strength because computational evidence does not support a deleterious 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 case reports with alternate diagnoses are available. Therefore, this criterion is not applied at Not Applied strength.
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: ClinVar reports Uncertain Significance, not benign. Therefore, this criterion is not applied at Not Applied strength.
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: p.E1060D is a missense change, not synonymous. Therefore, this criterion is not applied at Not Applied strength.