About KMT2A
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KMT2A c.7362T>C, p.(Thr2454=)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
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: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=7.07e-06 (2/282,756 alleles, 0 homozygotes) and gnomAD v4.1 AF=1.24e-06 (2/1,613,960 alleles, 0 homozygotes), well below the PM2 threshold of <0.1%. Absent from gnomAD-Canada.
Benign criteria applied · 2
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact. SpliceAI predicts no splice alteration (max delta=0.0; all four delta scores at 0.0). This is a synonymous variant with no predicted effect on splicing.
BP7Supporting
BP7 · supporting
This is a synonymous variant (p.Thr2454=) with no predicted splice impact. SpliceAI predicts no alteration to splice consensus sequences or creation of a new splice site (max delta=0.0; all four delta scores at 0.0). Nucleotide conservation data are not available; however, the SpliceAI prediction provides strong evidence for no splicing effect.
Recorded classification: Likely benign
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, BP7 supporting; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.
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
2 / 1,613,960 alleles
gnomAD v4.1: 2 / 1,613,960 alleles. Recorded AF 1.23919e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.07324e-06; MAF= 0.00071%, 2/282756 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.54909e-05; MAF= 0.00155%, 2/129108 alleles, homozygotes = 0).
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 identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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: 3 met · 5 not met · 12 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.7362T>C is a synonymous variant (p.Thr2454=) in KMT2A. KMT2A loss-of-function variants cause Wiedemann-Steiner syndrome (autosomal dominant).
This variant is present at extremely low frequency in population databases (gnomAD v2.1: 2/282,756 alleles, AF=7.07e-06; gnomAD v4.1: 2/1,613,960 alleles, AF=1.24e-06), meeting PM2 at supporting level.
SpliceAI predicts no splice impact (max delta=0.0; all four delta scores at 0.0), supporting a benign interpretation under BP4 and BP7.
No pathogenic in silico predictions are available; REVEL and BayesDel scores were not found for this variant. No computational evidence supports a deleterious effect (PP3 not met).
The variant is absent from ClinVar and no literature reports this specific variant. OncoKB lists classification as 'Unknown Oncogenic Effect' with no supporting evidence.
Applying generic ACMG/AMP 2015 combination rules: PM2 (supporting pathogenic) is outweighed by BP4 (supporting benign) and BP7 (supporting benign), yielding a classification of Likely Benign (2 supporting benign criteria).
No criteria match.
Met · 3
PM2 SupportingThis variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=7.07e-06 (2/282,756 alleles, 0 homozygotes) and gnomAD v4.1 AF=1.24e-06 (2/1,613,960 alleles, 0 homozygotes), well below the PM2 threshold of <0.1%. Absent from gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 2/282
- 756 alleles (AF=0.0007%)
- highest in NFE subpopulation (AF=0.00155%)
- gnomAD v4.1: 2/1
- 613
- 960 alleles (AF=0.00012%)
- NFE (AF=0.00017%)
- grpmax FAF=2.8e-07
- gnomAD-Canada: absent
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact. SpliceAI predicts no splice alteration (max delta=0.0; all four delta scores at 0.0). This is a synonymous variant with no predicted effect on splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta=0.0 (DS_AG=0.0
- DS_AL=0.0
- DS_DG=0.0
- DS_DL=0.0)
- Synonymous variant with no in silico prediction of splicing disruption
Sources
BP7 SupportingThis is a synonymous variant (p.Thr2454=) with no predicted splice impact. SpliceAI predicts no alteration to splice consensus sequences or creation of a new splice site (max delta=0.0; all four delta scores at 0.0). Nucleotide conservation data are not available; however, the SpliceAI prediction provides strong evidence for no splicing effect. Details ▾Hide ▴
Evidence considered
- Synonymous variant p.(Thr2454=)
- no amino acid change
- SpliceAI max delta=0.0
- DS_AG=0.0
- DS_AL=0.0
- DS_DG=0.0
- DS_DL=0.0
- No creation of cryptic splice site predicted
Still missing
- Nucleotide evolutionary conservation data not available
- BP7 ideally requires confirmation the nucleotide is not highly conserved
Sources
Not met · 5 · evaluated, threshold not reached
PM1 This variant does not lie in a statistically significant mutational hotspot and is not located in a well-established critical functional domain without benign variation. Details ▾Hide ▴
Evidence considered
- Hotspot analysis confirms variant is not in a statistically significant hotspot region
PP3 No pathogenic in silico predictions are available. REVEL and BayesDel scores were not found for this variant. SpliceAI predicts no splice impact (max delta=0.0). No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.0 (DS_AG=0.0
- DS_AL=0.0
- DS_DG=0.0
- DS_DL=0.0)
- REVEL score not available for this variant
- BayesDel score not available for this variant
Still missing
- REVEL and BayesDel scores unavailable
- limited in silico assessment
Sources
PP5 No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar. OncoKB reports classification as 'Unknown Oncogenic Effect' which does not constitute an assertion of pathogenicity. Details ▾Hide ▴
BA1 gnomAD allele frequency is far below the BA1 threshold of >1%. Highest observed population frequency is 1.55e-05 (NFE, v2.1) and overall AF is 7.07e-06 in v2.1 and 1.24e-06 in v4.1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 overall AF=0.0007%
- gnomAD v4.1 overall AF=0.00012%
- both well below BA1 threshold of >1%
Sources
BS1 gnomAD allele frequency is far below the BS1 threshold of >0.3%. Highest population AF is 0.00155% (NFE, v2.1). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 NFE AF=0.00155%
- gnomAD v4.1 NFE AF=0.00017%
- both well below BS1 threshold of >0.3%
Sources
Not assessed · 12 · no assessment recorded
PS2 No de novo data available. Literature search returned no PMIDs and no full-text publications were identified for this variant. Details ▾Hide ▴
Still missing
- No de novo testing data or published de novo reports available for this variant
PS3 No functional studies identified. Literature search returned no PMIDs; OncoKB lists classification as 'Unknown Oncogenic Effect' with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB reports Unknown Oncogenic Effect with no supporting functional PMIDs
Still missing
- No well-established in vitro or in vivo functional studies available for this variant
Sources
PS4 No case-control or statistical enrichment data available. This variant is absent from ClinVar and has no published case reports. Details ▾Hide ▴
Still missing
- No case-control studies or statistical enrichment data for this variant
PM6 No de novo data available. Literature search returned no PMIDs for this variant. Details ▾Hide ▴
Still missing
- No de novo observation data with confirmed maternity/paternity available
PP1 No co-segregation data available. No family studies or published pedigrees were identified for this variant. Details ▾Hide ▴
Still missing
- No co-segregation data in affected families
PP4 No patient phenotype or clinical data were provided for assessment. No published case reports describing this variant in affected individuals were identified. Details ▾Hide ▴
Still missing
- No patient phenotype data or clinical information available
BS2 No data available for observation in healthy adult controls. While the variant is observed in 2 individuals in gnomAD (a population database enriched for apparently healthy individuals), this alone is insufficient for BS2 without detailed phenotype confirmation. Details ▾Hide ▴
Evidence considered
- gnomAD observation in 2 individuals but no phenotype data available to confirm healthy adult status
Still missing
- No confirmed observation in healthy adult controls with full penetrance window
BS3 No functional studies demonstrating no deleterious effect have been identified. No literature or experimental data available for this variant. Details ▾Hide ▴
Still missing
- No well-established functional studies demonstrating no damaging effect
BS4 No segregation data available. No family studies demonstrating lack of segregation with disease were identified. Details ▾Hide ▴
Still missing
- No segregation data in affected families
BP2 No data available on observation in trans with a pathogenic variant in this autosomal dominant disorder. Details ▾Hide ▴
Still missing
- No data on co-occurrence with pathogenic variants in trans
BP5 No data available on an alternative molecular basis for disease in cases harboring this variant. Details ▾Hide ▴
Still missing
- No data on alternative molecular cause in individuals with this variant
BP6 Variant is absent from ClinVar; no reputable source has classified this variant as benign. Details ▾Hide ▴
Evidence considered
- ClinVar: no entries
- no classifications available
Still missing
- No reputable source classification available
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_005933.3:c.7362T>C is a synonymous variant (p.Thr2454=) that does not fall into a null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable to synonymous variants. Details ▾Hide ▴
Evidence considered
- Synonymous substitution with no predicted amino acid change (NP_005924.2:p.(Thr2454=))
- PVS1 variant assessment confirms variant bucket='other'
- apply_generic_pvs1_framework=false
Sources
pvs1_variant_assessmentpvs1_gene_context
PS1 N/APS1 requires a same amino acid change as an established pathogenic variant. This variant is synonymous (p.Thr2454=) and produces no amino acid change. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- no amino acid change to compare
PM3 N/APM3 applies to recessive disorders; KMT2A-associated Wiedemann-Steiner syndrome is autosomal dominant. No recessive disease context identified. Details ▾Hide ▴
Evidence considered
- Autosomal dominant disorder
- PM3 requires recessive inheritance context
PM4 N/APM4 applies to protein length changes from in-frame indels, stop-loss, or initiation codon variants. This is a synonymous single-nucleotide substitution with no protein length alteration. Details ▾Hide ▴
Evidence considered
- Synonymous substitution
- no protein length change
PM5 N/APM5 requires a different missense change at the same residue as an established pathogenic missense variant. This variant is synonymous (p.Thr2454=) and causes no amino acid change; PM5 candidate harvesting was unable to parse missense residue context. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- no amino acid change at residue 2454 for comparator analysis
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes where missense variants are a common mechanism and benign missense variation is low. This variant is synonymous (p.Thr2454=), not missense. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- PP2 is specific to missense variation
BP1 N/ABP1 applies to missense variants in genes where truncating variants are a known mechanism of disease. This variant is synonymous (p.Thr2454=), not missense. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- BP1 is specific to missense variation
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a single-nucleotide substitution. Details ▾Hide ▴
Evidence considered
- Substitution variant
- BP3 is specific to in-frame indels
PS5 N/AVariant is absent from ClinVar; no expert panel or reputable source has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar search returned no matching variation IDs or submissions
Sources
Identifiers
- Gene
- KMT2A
- Transcript
- NM_005933.3
- Coding (HGVS c.)
- NM_005933.3:c.7362T>C
- Protein (HGVS p.)
- NP_005924.2:p.(Thr2454=)
- GRCh38
- chr11:118503263 T>C
- GRCh37
- chr11:118373978 T>C
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
2 / 1,613,960 alleles
AF 1.24e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1
2 / 282,756 alleles
AF 7.07e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,613,960 alleles · 0 hom · FAF 2.8e-07
| European (non-Finnish)2 / 1,180,022 | 1.7e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 7.1e-06 · 2 / 282,756 alleles · 0 hom
| European (non-Finnish)2 / 129,108 | 1.5e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.23919e-06; MAF= 0.00012%, 2/1613960 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69488e-06; MAF= 0.00017%, 2/1180022 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.07324e-06; MAF= 0.00071%, 2/282756 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.54909e-05; MAF= 0.00155%, 2/129108 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact. SpliceAI predicts no splice alteration (max delta=0.0; all four delta scores at 0.0). This is a synonymous variant with no predicted effect on splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta=0.0 (DS_AG=0.0
- DS_AL=0.0
- DS_DG=0.0
- DS_DL=0.0)
- Synonymous variant with no in silico prediction of splicing disruption
Sources
BP7 SupportingThis is a synonymous variant (p.Thr2454=) with no predicted splice impact. SpliceAI predicts no alteration to splice consensus sequences or creation of a new splice site (max delta=0.0; all four delta scores at 0.0). Nucleotide conservation data are not available; however, the SpliceAI prediction provides strong evidence for no splicing effect. Details ▾Hide ▴
Evidence considered
- Synonymous variant p.(Thr2454=)
- no amino acid change
- SpliceAI max delta=0.0
- DS_AG=0.0
- DS_AL=0.0
- DS_DG=0.0
- DS_DL=0.0
- No creation of cryptic splice site predicted
Still missing
- Nucleotide evolutionary conservation data not available
- BP7 ideally requires confirmation the nucleotide is not highly conserved
Sources
PP3 No pathogenic in silico predictions are available. REVEL and BayesDel scores were not found for this variant. SpliceAI predicts no splice impact (max delta=0.0). No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.0 (DS_AG=0.0
- DS_AL=0.0
- DS_DG=0.0
- DS_DL=0.0)
- REVEL score not available for this variant
- BayesDel score not available for this variant
Still missing
- REVEL and BayesDel scores unavailable
- limited in silico assessment
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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
2 / 1,613,960 recorded alleles
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.7362T%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-118373978-T-C?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-118503263-T-C?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-118503263-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005933.3%3Ac.7362…
- OncoKB ↗www.oncokb.org/gene/KMT2A/T2454=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=KMT2A+c.7362T%3EC
- 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
This variant is present in gnomAD v4.1 (AF= 1.23919e-06; MAF= 0.00012%, 2/1613960 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69488e-06; MAF= 0.00017%, 2/1180022 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.07324e-06; MAF= 0.00071%, 2/282756 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.54909e-05; MAF= 0.00155%, 2/129108 alleles, homozygotes = 0).
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).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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.