About KMT2A
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KMT2A c.8878G>T, p.(Val2960Leu)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 (exome) and gnomAD v4.1 (exome) population databases, consistent with PM2 under generic ACMG/AMP 2015 interpretation.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence predict no deleterious impact. REVEL score is 0.178 (below 0.5 pathogenic threshold), BayesDel score is -0.147545 (negative score indicates benign), and SpliceAI predicts no splice impact (max delta score 0.00).
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 18 not met · 0 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_005933.3:c.8878G>T (p.Val2960Leu) is a missense variant in exon 27 of KMT2A.
This variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).
Multiple lines of computational evidence predict no deleterious effect: REVEL score 0.178, BayesDel score -0.147545, and SpliceAI max delta 0.00 (BP4_Supporting).
The variant is absent from ClinVar; no pathogenic or benign classification has been assigned by any clinical submitter.
No functional studies, segregation data, de novo observations, or case reports were identified for this specific variant in the literature.
Under generic ACMG/AMP 2015 combination rules, PM2_Supporting and BP4_Supporting are in opposing directions and do not combine to reach a conclusive classification. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 (exome) and gnomAD v4.1 (exome) population databases, consistent with PM2 under generic ACMG/AMP 2015 interpretation. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1 (search_status: absent).
- Absent from gnomAD-Canada v1.0.
Still missing
- Specific allele count (AC) and allele number (AN) were not captured from the gnomAD screens
- the pipeline reports absence but exact coverage at this position was not quantified.
Sources
BP4 SupportingMultiple lines of computational evidence predict no deleterious impact. REVEL score is 0.178 (below 0.5 pathogenic threshold), BayesDel score is -0.147545 (negative score indicates benign), and SpliceAI predicts no splice impact (max delta score 0.00). Details ▾Hide ▴
Evidence considered
- REVEL: 0.178. BayesDel: -0.147545. SpliceAI max delta: 0.00.
Sources
Not met · 18 · evaluated, threshold not reached
PS2 No evidence of de novo occurrence for NM_005933.3:c.8878G>T. No case reports, cohort studies, or clinical testing data confirming de novo status were identified in the literature or ClinVar. Details ▾Hide ▴
Evidence considered
- No de novo confirmation in ClinVar submissions
- no PMIDs identified in literature pass.
Still missing
- De novo testing data for this variant have not been reported.
Sources
PS3 No well-established in vitro or in vivo functional studies demonstrating a damaging effect on the gene or gene product were identified for this variant. OncoKB reports Unknown Oncogenic Effect. REVEL score of 0.178 and BayesDel score of -0.147545 are below thresholds for predicting deleterious impact. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence curated. REVEL: 0.178. BayesDel: -0.147545.
Still missing
- No functional studies have been published for this variant.
Sources
PS4 The prevalence of this variant in affected individuals has not been established. The variant is absent from ClinVar and no case-control studies or affected cohort data are available to demonstrate enrichment in cases over controls. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no case reports or cohort data identified.
Still missing
- No affected individual case data or case-control studies available.
Sources
PM1 The variant does not lie in a known mutational hotspot or a critical functional domain with a statistically significant enrichment of pathogenic variation. Residue p.Val2960 is not listed as a significant hotspot by Cancer Hotspots, and ClinVar does not show pathogenic variants clustered at this position. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue not significant. ClinVar: no pathogenic variants mapped to this residue.
Sources
PM6 No confirmed de novo observation for this variant was identified in the literature. PM6 requires a de novo observation with confirmed maternity and paternity, which is not available for NM_005933.3:c.8878G>T. Details ▾Hide ▴
Evidence considered
- No literature reports with de novo confirmation for this variant.
Still missing
- No de novo testing has been reported.
PP1 No cosegregation data with disease in multiple affected family members is available for this variant. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data identified.
Still missing
- No segregation or family study data available.
PP2 HCI prior is not supported for the KMT2A gene (gene_not_supported). No gene-specific missense constraint metric is available to determine whether missense variants are a common mechanism of disease for this gene. Details ▾Hide ▴
Evidence considered
- HCI prior: not found
- gene KMT2A not supported by HCI prior database.
Still missing
- No validated gene-specific missense constraint metric is available for KMT2A.
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.178 (below the 0.5 pathogenic threshold), BayesDel score is -0.147545 (negative score indicates benign), and SpliceAI predicts no splice impact (max delta score 0.00). Details ▾Hide ▴
Evidence considered
- REVEL: 0.178 (benign-leaning). BayesDel: -0.147545 (benign-leaning). SpliceAI delta: 0.00.
Sources
PP4 No patient phenotype data specific to this variant are available. No case reports describe the clinical presentation of an individual harboring NM_005933.3:c.8878G>T to allow assessment of phenotypic fit with KMT2A-related Wiedemann-Steiner syndrome. Details ▾Hide ▴
Evidence considered
- No case reports or clinical phenotype data for this variant identified.
Still missing
- No patient-specific phenotype data available.
PP5 The variant is absent from ClinVar. No reputable source (clinical diagnostic laboratory, expert panel) has classified this variant as pathogenic. Details ▾Hide ▴
BA1 The variant is absent from gnomAD population databases. Allele frequency is not >1%, which is the threshold for BA1. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v2.1 and v4.1
- allele frequency is effectively 0%.
Sources
BS1 The variant is absent from gnomAD population databases. Allele frequency is not >0.3%, which is the threshold for BS1. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v2.1 and v4.1
- allele frequency is effectively 0%.
Sources
BS2 No data are available on healthy adult controls carrying this variant. BS2 requires observation in healthy adults for a fully penetrant dominant disorder, which has not been reported for NM_005933.3:c.8878G>T. Details ▾Hide ▴
Evidence considered
- No healthy adult control data with this variant available.
Still missing
- No control population data specific to this variant.
BS3 No well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing have been identified for this variant. While in silico predictors are benign-leaning, BS3 requires experimental functional evidence, which is absent. Details ▾Hide ▴
Evidence considered
- No functional studies for this variant in any source.
Still missing
- No experimental functional data available.
Sources
BS4 No segregation data demonstrating lack of cosegregation with disease are available for this variant. Details ▾Hide ▴
Evidence considered
- No non-segregation data identified.
Still missing
- No family segregation data available.
BP2 No observation of this variant in trans with a known pathogenic variant in a gene associated with a recessive disorder has been reported. Details ▾Hide ▴
Evidence considered
- No data on variant phase with pathogenic variants.
Still missing
- No phase information available.
BP5 No alternative molecular basis for disease has been identified in a case harboring this variant. BP5 requires a stronger pathogenic variant explaining the phenotype in the same individual, which has not been reported for this variant. Details ▾Hide ▴
Evidence considered
- No case data available to assess alternative molecular causes.
Still missing
- No case-level data available.
BP6 No reputable source classifies this variant as benign or likely benign. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_005933.3:c.8878G>T is a missense variant (p.Val2960Leu). PVS1 is reserved for null variants (nonsense, frameshift, or canonical ±1,2 splice consensus). This variant does not fall into any of those categories. Details ▾Hide ▴
Evidence considered
- Missense variant classified as variant_bucket: other by PVS1 assessment
- apply_generic_pvs1_framework: false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ANo known pathogenic variant at the same amino acid position (p.Val2960) with the same amino acid change is available for comparison. The variant is absent from ClinVar, and no comparator exists to support that a different nucleotide change at this position resulting in the same missense change has been established as pathogenic. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no same-residue pathogenic comparator identified.
Sources
clinvar ↗pm5_candidates
PM3 N/AKMT2A-associated disease (Wiedemann-Steiner syndrome) is an autosomal dominant disorder. PM3 applies to recessive disorders. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AThis variant is a substitution, not a protein-length-altering variant (in-frame deletion/insertion or stop-loss). Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo other pathogenic missense variant at the same amino acid residue (p.Val2960) was identified in ClinVar. PM5 requires a different pathogenic missense change at the same residue as supporting evidence, which is not available. Details ▾Hide ▴
Evidence considered
- pm5_candidates returned 0 same-residue candidates
- eligible_for_classic_pm5_search: false.
Sources
pm5_candidates
BP1 N/ABP1 applies to missense variants in genes where only truncating variants are established as disease-causing. KMT2A-associated Wiedemann-Steiner syndrome is caused by both truncating and missense variants; therefore, a missense variant in KMT2A does not meet BP1 criteria. Details ▾Hide ▴
Evidence considered
- KMT2A disease mechanism includes both loss-of-function and missense variants
- haploinsufficiency is the primary mechanism.
- PMID:42196149 states: 'Most pathogenic KMT2A variants arise de novo and are typically nonsense or frameshift
- however
- missense variants have also been reported.'
Sources
pvs1_gene_context
BP3 N/AThis variant is a substitution, not an in-frame insertion/deletion in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies exclusively to synonymous (silent) variants for which splicing prediction algorithms predict no impact. NM_005933.3:c.8878G>T is a missense variant (p.Val2960Leu) and is not eligible for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant (substitution)
- not a synonymous change.
PS5 N/ANo de novo report exists for this variant (with both maternity and paternity confirmed). PS5 requires a reported de novo observation in the literature. Details ▾Hide ▴
Evidence considered
- No literature reports describing a de novo occurrence of this variant.
Identifiers
- Gene
- KMT2A
- Transcript
- NM_005933.3
- Coding (HGVS c.)
- NM_005933.3:c.8878G>T
- Protein (HGVS p.)
- NP_005924.2:p.(Val2960Leu)
- GRCh38
- chr11:118504779 G>T
- GRCh37
- chr11:118375494 G>T
Gene diagram
Every interpreted variant in KMT2A, mapped onto the exon structure of NM_005933.3. Select a row to find it on the plot.
KMT2ANM_005933.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in KMT2A
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.178
- BayesDel
- -0.148
How the predictions were used
BP4 SupportingMultiple lines of computational evidence predict no deleterious impact. REVEL score is 0.178 (below 0.5 pathogenic threshold), BayesDel score is -0.147545 (negative score indicates benign), and SpliceAI predicts no splice impact (max delta score 0.00). Details ▾Hide ▴
Evidence considered
- REVEL: 0.178. BayesDel: -0.147545. SpliceAI max delta: 0.00.
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.178 (below the 0.5 pathogenic threshold), BayesDel score is -0.147545 (negative score indicates benign), and SpliceAI predicts no splice impact (max delta score 0.00). Details ▾Hide ▴
Evidence considered
- REVEL: 0.178 (benign-leaning). BayesDel: -0.147545 (benign-leaning). SpliceAI delta: 0.00.
Sources
BP7 N/ABP7 applies exclusively to synonymous (silent) variants for which splicing prediction algorithms predict no impact. NM_005933.3:c.8878G>T is a missense variant (p.Val2960Leu) and is not eligible for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant (substitution)
- not a synonymous change.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.178. BayesDel score = -0.147545.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_005933.3%3Ac.8878G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-118375494-G-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-118504779-G-T?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-118504779-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005933.3%3Ac.8878…
- OncoKB ↗www.oncokb.org/gene/KMT2A/V2960L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=KMT2A+c.8878G%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.178. BayesDel score = -0.147545.
Functional
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
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.