KMT2A c.306_307delinsAA, p.Pro103Thr
NM_005933.3:c.306_307delinsAA
Variant of Uncertain Significance (VUS)
This missense variant p.P103T in KMT2A is absent from population databases (PM2 Moderate), shows computational evidence of no impact (BP4 Supporting), and is a missense in a gene where loss of function is the known mechanism (BP1 Supporting). No additional evidence supports pathogenicity or benign classification, resulting in a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
BP1
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.306_307delinsAA
Protein Change
P103T
Location
Exon 1
(Exon 1 of 36)
5'Exon Structure (36 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 103 in gene KMT2A
Variant interpretation based on transcript NM_005933.4
Genome Browser
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HGVS InputNM_005933:c.306_307delinsAA
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 103 in gene KMT2A
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
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 is a known mechanism of disease'. The evidence for this variant shows: 'c.306_307delinsAA results in a missense change P103T, not a null variant'. Therefore, this criterion is not applied because the variant does not result in a null effect.
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 reported pathogenic variant resulting in P103T'. Therefore, this criterion is not applied because there is no known established pathogenic variant at this residue.
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 data on de novo occurrence'. Therefore, this criterion is not applied due to lack of parental testing data.
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'. Therefore, this criterion is not applied because functional data are missing.
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 available'. Therefore, this criterion is not applied due to lack of statistical 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: 'P103 is not within a recognized hotspot or critical functional domain'. Therefore, this criterion is not applied.
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: 'Variant not found in gnomAD or other population databases'. 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 information on zygosity or trans configuration with another variant'. Therefore, this criterion is not applied.
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 without change in protein length'. Therefore, this criterion is not applied.
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 pathogenic missense changes reported at residue P103'. 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 de novo data 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 reported'. Therefore, this criterion is not applied.
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 primarily loss of function rather than 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'. The evidence for this variant shows: 'In silico tools and SpliceAI predict no impact'. 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 is highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: 'No phenotype or family data 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: 'No external pathogenic assertions found'. 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 (>5%)'. The evidence for this variant shows: 'Absent from population databases'. 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: 'Absent from population databases'. Therefore, this criterion is not applied.
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 disorder with full penetrance expected at an early age'. The evidence for this variant shows: 'No healthy adult observation data'. 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: 'No functional studies have been performed'. 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: 'No segregation data available'. Therefore, this criterion is not applied.
BP1
BP1 (Supporting)
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 pathogenic mechanism is primarily loss of function and missense is not established'. Therefore, this criterion is applied at Supporting 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 a dominant disorder'. The evidence for this variant shows: 'No data on co-occurrence with another variant'. 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: 'Not located in a repetitive region'. Therefore, this criterion is not applied.
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: 'SpliceAI and other in silico tools predict no effect'. Therefore, this criterion is applied at Supporting strength.
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 diagnosis 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: 'No benign assertions found'. 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: 'This is a missense variant, not synonymous'. Therefore, this criterion is not applied.