The DNMT3A NM_022552.5:c.2645G>A (NP_072046.2:p.(Arg882His)) missense variant has previously been reported in somatic cancers (COSMIC; COSV53036153, n = 1090 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: Exact p.Arg882His showed reduced methyltransferase activity, greater than 80% inhibition in mixed complexes, impaired processivity, and concordant cellular and murine effects. Based on available guidelines, this variant is considered to be Likely Pathogenic.
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.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.DNMT3A encodes an enzyme that adds new DNA methylation marks, helping control which genes are active during development and maintain normal genomic regulation. Germline changes in DNMT3A can cause Tatton-Brown-Rahman overgrowth syndrome, which includes intellectual disability. DNMT3A is also frequently altered in blood cancers, especially acute myeloid leukemia, and acts as a tumor suppressor in cancer.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, strong: exact p.Arg882His showed reduced methyltransferase activity, greater than 80% inhibition in mixed complexes, impaired processivity, and concordant cellular and murine effects.
Met, moderate: Arg882 is a recurrent DNMT3A AML hotspot within the catalytic domain, with R882H the most frequent reported substitution.
Met: the exact variant is reported de novo in an affected individual, but maternity and paternity confirmation is unavailable.
Met at supporting strength: missense REVEL 0.742 meets the generic PP3 threshold of >=0.644 but is below the moderate threshold of >=0.773.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS3 strong plus PM1 moderate, PM6 supporting, and PP3 supporting satisfy the generic ACMG/AMP fallback rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 427 / 1,612,436 alleles. Recorded AF 0.000264817. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0.000226626; MAF= 0.02266%, 64/282404 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000552043; MAF= 0.05520%, 11/19926 alleles, homozygotes = 0); grpmax FAF= 0.00033421.
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027179821700369644, 5/18396 alleles, homozygotes = 0).
Recorded REVEL score: 0.742. Refer to the recorded PP3/BP4 rationale for interpretation.
9 Pathogenic · 5 Likely pathogenic · 1 Likely Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV53036153, n = 1090 times).
This variant lies in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 9 not met · 10 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Generic ACMG/AMP rules govern because no DNMT3A VCEP specification is present. The only criterion met in this group is PM1 at moderate strength, based on the Arg882 recurrent hotspot and catalytic-domain location.
Among the requested segregation and de novo criteria, the evidence supports PM6 but not PS2 because parental maternity and paternity confirmation is not documented.
No sufficient family-level data are available to assess PP1 or BS4.
No criterion in this group is met under the generic ACMG/AMP rules supplied for this case.
PS4 was specifically checked against the literature packet's PS4-indexed papers; the verified exact-variant study reports affected-case counts but no valid control comparison, and the other indexed papers lack verifiable extracts in the available source registry.
PP5 and BP6 were restricted to exact-variant ClinVar expert-panel classifications; the ClinVar audit reports zero expert-panel submissions.
For this missense variant, the governing generic rules select the REVEL path and exclude SpliceAI from PP3/BP4.
REVEL 0.742 meets the supplied PP3 supporting threshold of >=0.644 but is above all BP4 thresholds; BayesDel is not usable because no generic ACMG-strength calibration is established.
The variant is rare but present in both default all-comers gnomAD datasets: AF 0.000226626 in v2.1 and AF 0.000264817 in v4.1, with zero homozygotes.
The observed frequencies are below the supplied BA1 and BS1 defaults but exceed the supplied PM2 threshold; BA1, BS1, and PM2 are not met, while BS2 cannot be assessed without verified healthy-adult individual-level data.
No criteria match.
PS3 is met at strong strength. The exact DNMT3A p.Arg882His variant was evaluated in multiple orthogonal functional systems. Purified-protein assays demonstrated reduced methyltransferase activity, disrupted oligomerization, altered catalytic kinetics, faster DNA dissociation, and markedly reduced processivity. Co-expression and co-purification experiments demonstrated greater than 80% reduction of activity in mixed wild-type/R882H complexes. Independent cellular and murine studies showed impaired DNA methylation, dominant-negative inhibition of endogenous DNMT3A/DNMT3B, abnormal hematopoietic stem-cell behavior, impaired differentiation, and disease-relevant phenotypes. The evidence is variant-specific, biologically relevant, and reproducible across biochemical, cellular, and in vivo models, although the record does not document validation in a clinical diagnostic laboratory.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. ... Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.
DNMT3A p.Arg882His lies at Arg882 in the catalytic domain and at a recurrent AML mutational hotspot. The reviewed evidence reports that most DNMT3A AML mutations affect Arg882, identifies R882H as the most frequent change, and documents additional R882 substitutions; no benign variation in the R882 hotspot or catalytic-domain site is documented in the supplied evidence. This satisfies the generic PM1 hotspot/critical-domain requirement without relying on a VCEP-specific rule.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
The exact variant is reported as a de novo event in an affected individual with Tatton-Brown-Rahman syndrome, while the available record does not confirm maternity and paternity. This supports PM6, which applies to an assumed de novo variant without parental confirmation; the limited parental-testing documentation warrants human review.
Assumed de novo, but without confirmation of paternity and maternity.
The variant is a missense variant, NM_022552.5:c.2645G>A (p.Arg882His), so the generic missense path requires REVEL and excludes SpliceAI for PP3/BP4. The applicable REVEL score is 0.742, which meets the supplied generic PP3 supporting threshold of >=0.644 but is below the moderate threshold of >=0.773 and strong threshold of >=0.932. BayesDel has no established generic ACMG-strength calibration and is not used.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent
The variant is reported as de novo in at least one individual with Tatton-Brown-Rahman syndrome, but the available evidence does not document confirmation of both maternity and paternity. Under the PS2 definition, a de novo report without confirmed maternity and paternity does not meet PS2; it is considered under PM6 instead.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The governing ACMG/AMP PS4 definition requires a significantly increased prevalence in affected individuals compared with controls; the rule's quantitative note requires RR or OR >5.0 with a confidence interval that does not include 1.0. PMID:21067377 reports 27 R882H tumors among 281 AML patients, but it does not report unaffected/control R882H counts, a matched-ancestry control frequency, an OR/RR, or a confidence interval. I therefore did not compute an OR from the AML case count against gnomAD, because the AML observations are somatic tumor findings and gnomAD is a population germline dataset rather than a matched case-control comparator. The literature packet's PS4 index entries for PMID:21956720, PMID:23169492, and PMID:33226740 were not accompanied by an abstract or full-text extract in the available source registry, so they do not establish case-control evidence. No valid case-control comparison meeting the rule is present.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
The variant is present in default all-comers gnomAD v2.1 at AF 0.000226626 and gnomAD v4.1 at AF 0.000264817, both exceeding the supplied generic PM2 supporting threshold of <=0.0001. It is also observed in multiple subpopulations, so PM2 is not met.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
The governing PP5 definition concerns a reputable source reporting the variant as pathogenic when the underlying evidence is unavailable for independent evaluation. This case has no ClinVar expert-panel submission for the exact variant; the available assertions are laboratory or other non-expert submissions. In addition, the relevant published evidence is available for independent evaluation, so PP5 is not applied.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is present in default all-comers gnomAD v2.1 at AF 0.000226626 (64/282404 alleles) and gnomAD v4.1 at AF 0.000264817 (427/1612436 alleles), with zero homozygotes. These frequencies, including the highest observed subpopulation frequencies of 0.000552043 in v2.1 and 0.000507305 in v4.1, are far below the supplied BA1 stand-alone threshold of >=0.05; therefore BA1 is not met.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Default all-comers gnomAD reports AF 0.000226626 in v2.1 and 0.000264817 in v4.1; the highest observed subpopulation frequencies are 0.000552043 and 0.000507305, respectively. These values are below the supplied generic BS1 default of >=0.01 and do not establish a frequency greater than expected for the disorder. Because the observed frequency is far below the default, a separate maximum-credible-frequency calculation using prevalence, penetrance, and allelic heterogeneity inputs is not needed to reject BS1.
Allele frequency is greater than expected for disorder.
BS3 is not met. The available variant-specific functional evidence does not show no damaging effect on DNMT3A function or splicing; instead, independent biochemical, cellular, and in vivo studies demonstrate reduced methyltransferase activity, abnormal oligomerization or processivity, impaired DNA methylation, and disease-relevant cellular phenotypes. Therefore, the evidence cannot support a benign functional criterion.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The variant is a missense variant, so BP4 must be judged on the REVEL path only; SpliceAI cannot provide BP4 evidence for this protein-substituting variant. REVEL is 0.742, which is above the generic BP4 supporting cutoff of <=0.29, so BP4 is not met. BayesDel is not usable because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion.
The governing BP6 definition concerns a reputable source reporting the variant as benign when the underlying evidence is unavailable for independent evaluation. No exact-variant ClinVar expert-panel benign or likely benign classification is present, and the available exact-variant assertions are pathogenic or likely pathogenic rather than benign. Therefore BP6 is not applied.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The case evidence establishes the observed variant as DNMT3A p.Arg882His, but the reviewed literature reports this same c.2645G>A change and does not establish a previously pathogenic alternate nucleotide change producing p.Arg882His. The required same-amino-acid, different-nucleotide comparator is therefore not available for a definitive PS1 assessment.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
The reviewed AML cohort reports other missense substitutions at Arg882, specifically R882C, R882P, and R882S, but the supplied evidence does not establish any of those alternate missense variants as pathogenic under a documented clinical or expert-panel determination. Recurrent somatic occurrence alone is insufficient to apply PM5.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
The available evidence reports an apparently de novo occurrence but does not provide multiple affected family members, family genotypes, or meiosis-level segregation data. Therefore, co-segregation cannot be assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The supplied evidence documents recurrent DNMT3A missense changes and functional effects at Arg882, but it does not provide the gene-level evidence needed to establish both a low rate of benign missense variation and missense variation as a common disease mechanism for DNMT3A. The criterion cannot be assessed from the available evidence.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The governing rule requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The case evidence identifies DNMT3A p.Arg882His and literature relating it to Tatton-Brown-Rahman syndrome, but it does not provide the index patient's phenotype or family history in sufficient detail to determine whether the presentation is highly specific for that disorder.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
The population records report zero homozygotes but do not identify an individual, provide age or phenotype information, document clinical evaluation, or establish verified unaffected status. Therefore the specific healthy-adult observation required for BS2 cannot be assessed from these aggregate data.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
The available evidence does not identify affected relatives who lack the variant, nor does it provide a family pedigree or genotype-phenotype comparison. Lack of segregation therefore cannot be assessed, and no BS4 evidence is applied.
Lack of segregation in affected members of a family.
The supplied evidence shows recurrent DNMT3A missense disease-associated variation, especially at Arg882, but it does not provide a comprehensive gene-level assessment demonstrating that disease is caused primarily by truncating variants. The BP1 gene-mechanism requirement therefore remains unresolved.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
No qualifying observation of this variant with a second pathogenic variant is documented. The available evidence identifies this variant as heterozygous and reports de novo constitutional cases, but does not provide a second pathogenic variant in trans in a fully penetrant dominant disorder or a pathogenic variant in cis in any inheritance pattern. Phase and paired-variant data are therefore insufficient to assess BP2.
BP2: Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The governing BP5 definition requires the variant to be found in a case with an alternate molecular basis for disease. The available evidence reports DNMT3A p.Arg882His in AML and constitutional Tatton-Brown-Rahman syndrome contexts, but does not document an alternate molecular diagnosis in the case being adjudicated. The somatic AML observations are not, by themselves, an alternate molecular basis for this patient's disease.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_022552.5:c.2645G>A in DNMT3A is a missense substitution predicted to produce NP_072046.2:p.(Arg882His). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for DNMT3A, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM3 is not applicable because the documented constitutional DNMT3A-related disorder context is heterozygous and includes de novo observations, supporting a dominant rather than recessive inheritance model. No recessive disease mechanism or pathogenic variant in trans is documented for this individual. Therefore the recessive-disorder PM3 rule does not apply.
PM3: For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase.
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_022552.5:c.2645G>A in DNMT3A is a missense substitution predicted to produce NP_072046.2:p.(Arg882His). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for DNMT3A, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_022552.5:c.2645G>A in DNMT3A is a missense substitution predicted to produce NP_072046.2:p.(Arg882His). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for DNMT3A, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_022552.5:c.2645G>A in DNMT3A is a missense substitution predicted to produce NP_072046.2:p.(Arg882His). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for DNMT3A, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in DNMT3A, mapped onto the exon structure of NM_022552.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Ashkenazi Jewish15 / 29,568 | 0.00051 |
| African/African American34 / 74,814 | 0.00045 |
| European (non-Finnish)316 / 1,178,870 | 0.00027 |
| East Asian12 / 44,840 | 0.00027 |
| European (Finnish)14 / 63,958 | 0.00022 |
| South Asian19 / 91,008 | 0.00021 |
| Remaining individuals9 / 62,440 | 0.00014 |
| Admixed American8 / 59,948 | 0.00013 |
| East Asian11 / 19,926 | 0.00055 |
| African/African American13 / 24,926 | 0.00052 |
| Ashkenazi Jewish3 / 10,360 | 0.00029 |
| European (Finnish)6 / 25,104 | 0.00024 |
| South Asian7 / 30,562 | 0.00023 |
| European (non-Finnish)23 / 128,990 | 0.00018 |
| Remaining individuals1 / 7,212 | 0.00014 |
This variant is present in gnomAD v4.1 (AF= 0.000264817; MAF= 0.02648%, 427/1612436 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000507305; MAF= 0.05073%, 15/29568 alleles, homozygotes = 0); grpmax FAF= 0.00033406.
This variant is present in gnomAD v2.1 (AF= 0.000226626; MAF= 0.02266%, 64/282404 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000552043; MAF= 0.05520%, 11/19926 alleles, homozygotes = 0); grpmax FAF= 0.00033421.
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027179821700369644, 5/18396 alleles, homozygotes = 0).
The variant is a missense variant, NM_022552.5:c.2645G>A (p.Arg882His), so the generic missense path requires REVEL and excludes SpliceAI for PP3/BP4. The applicable REVEL score is 0.742, which meets the supplied generic PP3 supporting threshold of >=0.644 but is below the moderate threshold of >=0.773 and strong threshold of >=0.932. BayesDel has no established generic ACMG-strength calibration and is not used.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent
The variant is a missense variant, so BP4 must be judged on the REVEL path only; SpliceAI cannot provide BP4 evidence for this protein-substituting variant. REVEL is 0.742, which is above the generic BP4 supporting cutoff of <=0.29, so BP4 is not met. BayesDel is not usable because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion.
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_022552.5:c.2645G>A in DNMT3A is a missense substitution predicted to produce NP_072046.2:p.(Arg882His). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for DNMT3A, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.742. BayesDel score = 0.376858.
8 paper records listed. 5 cited in the classification.
A total of 27 tumors had the R882H variant, 7 had R882C, 2 had R882P, and 1 had R882S.
Location Results, DNMT3A Mutations in AML; Discussion
Context AML cohort of 281 patients; DNMT3A exon PCR and Sanger sequencing; MeDIP-chip methylation analysis of R882H AML genomes and matched AML genomes without DNMT3A mutations.
The AML mutant R882H had a 2.5-fold reduction in activity, also in agreement with previous studies (20).
Location Results: “Disruption of Dimer Interface Reduces Activity and Results in Altered Catalytic Properties”; Tables 2–5; Figures 3–6
Context In vitro biochemical assays using purified DNMT3A catalytic-domain protein, including oligomerization, methylation kinetics, DNA dissociation, processivity, and DNMT3L rescue experiments.
Mouse Dnmt3a R878H (human R882H) mutant protein inhibits wild-type Dnmt3a/Dnmt3b in murine ES cells, suggesting dominant-negative effects.
Location Key Point; Abstract; Results and Discussion, pages 5-7; Figures 1-2
Context Murine embryonic stem-cell re-methylation assays using Dnmt3a/Dnmt3b knockout or single-knockout ES cells; DNA methylation assessed at major satellite repeats and intracisternal A-particle retrotransposons by methylation-sensitive restriction/Southern analysis and bisulfite sequencing; protein interactions assessed by co-immunoprecipitation and pull-down assays.
Somatic mutations in DNMT3A, which encodes a de novo DNA methyltransferase, are found in ∼30% of normal karyotype acute myeloid leukemia (AML) cases. Most mutations are heterozygous and alter R882 within the catalytic domain (most commonly R882H), suggesting the possibility of dominant-negative consequences.
Location Abstract; Results, “Structural and Functional Consequences of the R882H Mutation in DNMT3A”
Context Primary NK-AML samples; recombinant full-length DNMT3A methyltransferase assays; co-expression and co-purification in HEK293T cells; methylation-array analysis of AML cases.
Expression of DNMT3AR882H reduced MOLM-13 cells’ sensitivity to daunorubicin (Supplementary Fig. 3c), and Dnmt3amut mouse embryonic fibroblasts (MEFs) showed reduced sensitivity to daunorubicin, but not to other DNA-damaging agents in vitro.
Location Results, page 3, paragraph describing AML cell-line and MEF drug-sensitivity experiments; related findings in Figures 2–4 and Supplementary Figures 3–7
Context Human AML cell lines and primary AML samples; ECOG-ACRIN E1900 cohort with 398 AML patients and paired diagnosis/post-induction samples; retroviral DNMT3A R882H expression assays; alkaline comet assay, western blot DNA-damage signaling assays, gene-expression analysis, chromatin and histone-eviction assays; conditional Dnmt3a R878H knock-in mouse model, the mouse homolog of human DNMT3A R882H.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.000264817; MAF= 0.02648%, 427/1612436 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000507305; MAF= 0.05073%, 15/29568 alleles, homozygotes = 0); grpmax FAF= 0.00033406.
This variant is present in gnomAD v2.1 (AF= 0.000226626; MAF= 0.02266%, 64/282404 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000552043; MAF= 0.05520%, 11/19926 alleles, homozygotes = 0); grpmax FAF= 0.00033421.
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027179821700369644, 5/18396 alleles, homozygotes = 0).
This variant has been reported in ClinVar as Pathogenic (9 clinical laboratories) and as Likely pathogenic (5 clinical laboratories) and as Likely Pathogenic (1 clinical laboratory). (ClinVarID = 375881)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.742. BayesDel score = 0.376858.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53036153, n = 1090 times).
This variant lies in a statistically significant hotspot.