About DNMT3A
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
DNMT3A c.1154del, p.(Pro385ArgfsTer22)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic 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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
NM_022552.4:c.1154delC is a frameshift deletion predicted to produce a premature termination codon at residue 406 (NP_072046.2:p.Pro385ArgfsTer22) in exon 10 of 22 coding exons. The variant is predicted to trigger nonsense-mediated decay. DNMT3A loss of function is an established disease mechanism for Tatton-Brown-Rahman syndrome (ClinGen haploinsufficiency score=3). Under ClinGen SVI PVS1 recommendations (PMC6185798), a null variant in a gene where LOF is a known mechanism qualifies for PVS1 at very strong level.
PM2Moderate
PM2 · moderate
NM_022552.4:c.1154delC is absent from gnomAD v2.1 (0/250,600 alleles) and present at extremely low frequency in gnomAD v4.1 (6/1,613,666 alleles, AF=3.72e-06). Complete absence from the v2.1 dataset and near-absence from v4.1 satisfies PM2 under generic ACMG guidelines at moderate strength.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
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
6 / 1,613,666 alleles
gnomAD v4.1: 6 / 1,613,666 alleles. Recorded AF 3.71824e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/250600 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16144 alleles, homozygotes = 0).
SpliceAI score
0.050 maximum delta
Recorded SpliceAI maximum delta score: 0.050. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
6 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV53048650, n = 6 times).
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.
28 criteria with recorded statuses: 2 met · 11 not met · 5 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PVS1 (very strong): NM_022552.4:c.1154delC is a frameshift deletion introducing a premature termination codon at position 406 (NP_072046.2:p.Pro385ArgfsTer22) in exon 10 of 22 coding exons, predicted to trigger nonsense-mediated decay. DNMT3A loss of function is an established disease mechanism for Tatton-Brown-Rahman syndrome, with a ClinGen haploinsufficiency score of 3.
PM2 (moderate): The variant is absent from gnomAD v2.1 (0/250,600 alleles) and present at extremely low frequency in gnomAD v4.1 (6/1,613,666 alleles; AF=3.72e-06). The highest subpopulation frequency is 1.67e-05 in the Admixed American population, well below the 0.1% PM2 threshold.
Combined classification: One very strong criterion (PVS1) and one moderate criterion (PM2) satisfy the Likely Pathogenic threshold under generic ACMG/AMP 2015 rules (1 Very Strong + 1 Moderate).
No criteria match.
Met · 2
PVS1 Very strongNM_022552.4:c.1154delC is a frameshift deletion predicted to produce a premature termination codon at residue 406 (NP_072046.2:p.Pro385ArgfsTer22) in exon 10 of 22 coding exons. The variant is predicted to trigger nonsense-mediated decay. DNMT3A loss of function is an established disease mechanism for Tatton-Brown-Rahman syndrome (ClinGen haploinsufficiency score=3). Under ClinGen SVI PVS1 recommendations (PMC6185798), a null variant in a gene where LOF is a known mechanism qualifies for PVS1 at very strong level. Details ▾Hide ▴
Evidence considered
- Frameshift deletion introducing PTC at codon 406 in exon 10/22
- predicted to trigger NMD
- DNMT3A LOF is an established mechanism for Tatton-Brown-Rahman syndrome (ClinGen haploinsufficiency score=3)
- NM_022552.4 is a RefSeq select transcript biologically relevant for DNMT3A
Sources
PM2 ModerateNM_022552.4:c.1154delC is absent from gnomAD v2.1 (0/250,600 alleles) and present at extremely low frequency in gnomAD v4.1 (6/1,613,666 alleles, AF=3.72e-06). Complete absence from the v2.1 dataset and near-absence from v4.1 satisfies PM2 under generic ACMG guidelines at moderate strength. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0/250
- 600 alleles (completely absent)
- gnomAD v4.1: 6/1
- 613
- 666 alleles (AF=3.72e-06)
- Highest subpopulation frequency: AMR at 1.67e-05 (well below 0.1% PM2 threshold)
Sources
Not met · 11 · evaluated, threshold not reached
PS2 PS2 requires a de novo occurrence with confirmed paternity and maternity. No de novo reports were identified for NM_022552.4:c.1154delC in ClinVar or the reviewed literature. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no de novo submissions found
- No de novo reports in reviewed literature
Still missing
- De novo status could exist in unpublished clinical data
Sources
PS4 PS4 requires a statistically significant enrichment of the variant in affected individuals compared with controls. No case-control studies or multiple unrelated probands with this variant were identified. The variant is absent from ClinVar and not reported in the reviewed literature. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- Variant is extremely rare in gnomAD (0/250
- 600 in v2.1
- 6/1
- 613
- 666 in v4.1)
- No case series or case-control studies reporting this variant in affected individuals
Still missing
- No published case series or aggregate patient datasets for this variant
Sources
PM1 PM1 requires location in a mutational hot spot or critical functional domain without benign variation. The variant lies at residue 385 within the PWWP domain of DNMT3A, which is a functionally important region. However, Cancer Hotspots analysis did not identify a statistically significant mutational hotspot at this residue. Without a VCEP-specific domain specification for DNMT3A, PM1 cannot be confidently applied under generic ACMG. Details ▾Hide ▴
Evidence considered
- Residue 385 lies within the PWWP domain of DNMT3A
- Cancer Hotspots analysis: no statistically significant hotspot at this residue
- No VCEP/CSPEC guidance available for DNMT3A PM1 domains
Still missing
- No VCEP-defined critical domain boundaries for DNMT3A
PM6 PM6 requires an assumed de novo occurrence without confirmation of paternity and maternity. No such reports were identified for NM_022552.4:c.1154delC in ClinVar or the reviewed literature. Details ▾Hide ▴
Evidence considered
- No assumed de novo reports in ClinVar or literature
Still missing
- Possible unpublished clinical observations
Sources
PP1 PP1 requires cosegregation of the variant with disease in multiple affected family members. No family segregation data were identified for NM_022552.4:c.1154delC. Details ▾Hide ▴
Evidence considered
- No cosegregation data available
Still missing
- No family studies available for this variant
Sources
21067377246140702596425338937076
BA1 BA1 requires an allele frequency >1% in any general population. The highest observed frequency for NM_022552.4:c.1154delC is 1.67e-05 (0.00167%) in the Admixed American subpopulation of gnomAD v4.1, well below the 1% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 maximum subpopulation AF: 1.67e-05 (Admixed American)
- Well below 1% BA1 threshold
Sources
BS1 BS1 requires an allele frequency greater than expected for the disorder. The highest observed population frequency is 1.67e-05 (0.00167%), well below the 0.3% threshold. Tatton-Brown-Rahman syndrome is a rare disorder; this frequency is consistent with a rare pathogenic variant. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 maximum AF: 1.67e-05
- well below 0.3% BS1 threshold
- TBRS is a rare disorder
- inconsistent with a benign polymorphism at this frequency
Sources
BS2 BS2 requires observation of the variant in a healthy adult individual for a disorder with full penetrance expected at an early age. No such observations were identified for NM_022552.4:c.1154delC. Details ▾Hide ▴
Evidence considered
- No reports of this variant in healthy adults with full penetrance expected
BS3 BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. OncoKB annotation indicates a Likely Loss-of-function effect for this variant, which is inconsistent with a benign functional assessment. No studies demonstrating a neutral functional effect were identified. Details ▾Hide ▴
Evidence considered
- OncoKB annotated as Likely Loss-of-function (damaging
- not benign)
- No functional studies showing neutral effect identified
Sources
BS4 BS4 requires lack of segregation of the variant with disease in affected family members. No family segregation data were identified for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family studies available
BP2 BP2 requires observation of the variant in trans with a known pathogenic variant in a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern. No such observations were identified for NM_022552.4:c.1154delC. Details ▾Hide ▴
Evidence considered
- No trans or cis observations reported
Not assessed · 5 · no assessment recorded
PS3 PS3 requires well-established in vitro or in vivo functional studies demonstrating a damaging effect specific to this variant. OncoKB annotates this variant as Likely Loss-of-function in a somatic/oncogenic context, but no germline functional studies confirming a damaging effect for NM_022552.4:c.1154delC were identified. The variant type (frameshift with predicted NMD) already supports a null effect captured by PVS1; applying PS3 would constitute double-counting of the same evidence. Details ▾Hide ▴
Evidence considered
- OncoKB annotated as Likely Loss-of-function (somatic context)
- No variant-specific germline functional studies identified
Still missing
- No germline functional assay data for this specific variant
Sources
PP4 PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. No patient phenotype data were provided for this case. Details ▾Hide ▴
Still missing
- Patient phenotype data not provided for assessment
PP5 PP5 requires that a reputable source recently reports the variant as pathogenic but the evidence is not independently verifiable. No such source was identified. The variant is absent from ClinVar. Details ▾Hide ▴
BP5 BP5 requires that the variant is found in a case with an alternate molecular basis for disease. No such data were available for assessment. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available
BP6 BP6 requires that a reputable source reports the variant as benign but the evidence is not independently verifiable. No such source was identified. The variant is absent from ClinVar. Details ▾Hide ▴
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to nucleotide substitutions where a different change at the same position has been established as pathogenic. This variant is a single-nucleotide deletion, not a substitution. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. This variant is a frameshift deletion, which is assessed under PVS1 rather than PM4. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 applies to novel missense variants at the same residue as a known pathogenic missense change. This variant is a frameshift deletion, not a missense. Automated PM5 candidate harvesting confirmed ineligibility. Details ▾Hide ▴
Evidence considered
- Variant is a frameshift deletion
- not a missense change amenable to PM5 analysis
Sources
pm5_candidates
PP2 N/APP2 applies specifically to missense variants in genes with a low rate of benign missense variation where missense is a common disease mechanism. This variant is a frameshift deletion. Details ▾Hide ▴
No further detail was recorded.
PP3 N/APP3 applies to in silico prediction evidence for missense and splice variants. This is a frameshift deletion. SpliceAI predicts no significant splice impact (max delta=0.05), and REVEL/BayesDel are not applicable to non-SNV variants. The deleterious effect of a frameshift is already captured by PVS1; applying PP3 would constitute double-counting. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta=0.05 (no significant splice impact)
- REVEL/BayesDel not applicable for deletion variants
Sources
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This variant is itself a truncating (frameshift) variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions without known function. This variant is a frameshift deletion, not an in-frame change. Details ▾Hide ▴
No further detail was recorded.
BP4 N/ABP4 applies to computational evidence suggesting no impact on the gene product for missense and splice variants. This is a frameshift truncating variant. SpliceAI shows no splice effect (max delta=0.05), but the protein-level impact of a frameshift is assessed under PVS1. Applying BP4 would be inappropriate for a null variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta=0.05 (no splice effect)
- Frameshift impact on protein is assessed under PVS1
- not BP4
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted impact on splicing. This variant is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 applies to novel missense variants at a residue where a different pathogenic missense change has been reported. This variant is a frameshift deletion, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- DNMT3A
- Transcript
- NM_022552.4
- Coding (HGVS c.)
- NM_022552.4:c.1154del
- Protein (HGVS p.)
- NP_072046.2:p.(Pro385ArgfsTer22)
- GRCh38
- chr2:25246744 CG>C
- GRCh37
- chr2:25469613 CG>C
- COSMIC
- COSV53048650
Gene diagram
Every interpreted variant in DNMT3A, mapped onto the exon structure of NM_022552.4. Select a row to find it on the plot.
DNMT3ANM_022552.4
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 DNMT3A
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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
6 / 1,613,666 alleles
AF 3.72e-06 · 0 homozygotes · FAF 1.24e-06
gnomAD v2.1
0 / 250,600 alleles
AF 0 · 0 homozygotes
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 3.7e-06 · 6 / 1,613,666 alleles · 0 hom · FAF 1.2e-06
| Admixed American1 / 60,010 | 1.7e-05 |
| European (non-Finnish)5 / 1,179,996 | 4.2e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 0 · 0 / 250,600 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.71824e-06; MAF= 0.00037%, 6/1613666 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66639e-05; MAF= 0.00167%, 1/60010 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/250600 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16144 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 applies to in silico prediction evidence for missense and splice variants. This is a frameshift deletion. SpliceAI predicts no significant splice impact (max delta=0.05), and REVEL/BayesDel are not applicable to non-SNV variants. The deleterious effect of a frameshift is already captured by PVS1; applying PP3 would constitute double-counting. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta=0.05 (no significant splice impact)
- REVEL/BayesDel not applicable for deletion variants
Sources
BP4 N/ABP4 applies to computational evidence suggesting no impact on the gene product for missense and splice variants. This is a frameshift truncating variant. SpliceAI shows no splice effect (max delta=0.05), but the protein-level impact of a frameshift is assessed under PVS1. Applying BP4 would be inappropriate for a null variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta=0.05 (no splice effect)
- Frameshift impact on protein is assessed under PVS1
- not BP4
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted impact on splicing. This variant is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
3 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 21067377 ↗DNMT3A mutations in acute myeloid leukemia.No paper-specific finding is recorded.
-
PMID 24614070 ↗Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability.No paper-specific finding is recorded.
-
PMID 25964253 ↗Simpson's Paradox and the Impact of Different DNMT3A Mutations on Outcome in Younger Adults With Acute Myeloid Leukemia.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
6 / 1,613,666 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.050
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_022552.4%3Ac.1154delC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-25469613-CG-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-25246744-CG-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_022552.4%3Ac.1154…
- OncoKB ↗www.oncokb.org/gene/DNMT3A/P385Rfs*22
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121996050
- 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= 3.71824e-06; MAF= 0.00037%, 6/1613666 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66639e-05; MAF= 0.00167%, 1/60010 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/250600 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16144 alleles, homozygotes = 0).
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53048650, n = 6 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.