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.
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 Not recorded. 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, supporting: Asp702 lies in DNMT3A's MTase domain, where 81% of 140 tested variants showed little or no methyltransferase activity.
Met at supporting strength: gnomAD v4.1 total AF is 6.20e-7, below the generic PM2 threshold of 0.0001, with one allele and zero homozygotes.
Met, strong: REVEL 0.936 meets the calibrated strong PP3 threshold of >=0.932 for this missense variant.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PM1 (supporting), PM2 (supporting), and PP3 (strong) satisfy the generic ACMG/AMP fallback combination used by the deterministic derivation.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 1 / 1,614,170 alleles. Recorded AF 6.19513e-07. Recorded homozygote count 0.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
Recorded REVEL score: 0.936. Refer to the recorded PP3/BP4 rationale for interpretation.
A ClinVar laboratory submission summary was not recorded.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. DNMT3A, a tumor suppressor and DNA methyltransferase, is recurrently mutated in acute myeloid leukemia and other hematologic malignancies.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 7 not met · 14 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No DNMT3A-specific VCEP or gene-specific framework was available, so generic ACMG/AMP rules were used.
The strongest codon/domain evidence is supporting PM1 for location in the DNMT3A methyltransferase domain; PS1 is not met, while PM5, PP2, and BP1 remain unresolved because the required curated comparator or gene-level datasets are unavailable.
No DNMT3A-specific VCEP or gene-specific framework was retrieved; generic ACMG/AMP concepts were used only where applicable.
PS4, PP4, and BP5 lack the required patient-level or exact-variant evidence and are therefore not assessed.
PP5 and BP6 are not met because ClinVar contains no exact-variant expert-panel assertion for NM_022552.4:c.2106T>A.
Generic ACMG fallback applies because no DNMT3A-specific VCEP or CSPEC framework was available.
The missense consequence selects REVEL as the sole computational path for PP3 and BP4; SpliceAI is not double-counted or substituted.
Population evidence supports PM2 at supporting strength because the variant is absent from gnomAD v2.1 and extremely rare in gnomAD v4.1.
BA1 and BS1 are not met because the highest observed gnomAD v4.1 frequency is far below both generic benign-frequency thresholds.
BS2 is not met because the available population record does not provide phenotype-confirmed healthy-adult status or a qualifying homozygote observation.
No criteria match.
PM1 is met at supporting strength under the generic framework. DNMT3A p.Asp702Glu places residue 702 within the enzyme's C-terminal methyltransferase (MTase) domain, a recognized functional region. PMID:34429321 reports systematic functional testing of DNMT3A variants and specifically identifies the PWWP and MTase domains as regions in which most tested variants showed little or no methyltransferase activity (114 of 140 MTase-domain variants, 81%). No DNMT3A-specific VCEP domain table was available; therefore the generic domain evidence is used, and human review is appropriate to confirm the domain boundary and PM1 applicability.
Generic ACMG/AMP PM1: variant located in a critical and well-established functional domain or hotspot, with benign variation absent or uncommon; no applicable gene-specific specification was available.
No applicable DNMT3A VCEP or gene-specific framework was available, so the supplied generic PM2 threshold applies. The variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1, with total AF 6.195134341488195e-07 (1/1,614,170 alleles), highest subpopulation AF 8.474389547348956e-07, and zero homozygotes. These frequencies are below the generic PM2 supporting threshold of <=0.0001. No non-cancer subset result was available, but no governing specification required that subset.
Generic PM2: allele frequency <=0.0001, applied at supporting strength; use the governing VCEP population source when one exists.
The variant is a missense substitution, NM_022552.4:c.2106T>A (p.Asp702Glu), so PP3 is evaluated using the missense REVEL path only. REVEL is 0.936, which meets the generic ClinGen SVI strong PP3 threshold of >=0.932 from the Pejaver et al. 2022 calibration (PMID:36413997). SpliceAI and BayesDel are not used for this criterion: SpliceAI is the non-missense path and BayesDel has no generic ACMG strength calibration. No governing DNMT3A VCEP specification was available.
generic_acmg_revel_pp3_strong
PS1 is not met. The variant is DNMT3A NP_072046.2:p.(Asp702Glu), and the available exact-variant records show no ClinVar entry. The fetched DNMT3A functional profiling paper explicitly states that p.Asp702Glu was not mentioned, so there is no established pathogenic same-amino-acid change to support PS1.
Generic ACMG/AMP PS1: same amino-acid change as an established pathogenic variant; no applicable gene-specific specification was available.
PP5 is restricted here to an exact-variant ClinVar expert-panel assertion of Pathogenic or Likely pathogenic. The exact variant NM_022552.4:c.2106T>A (NP_072046.2:p.Asp702Glu) was not found in ClinVar, with no variation ID, expert-panel review status, or expert-panel classification. Gene-level OncoKB context and the PMID:34429321 publication are not exact-variant ClinVar expert-panel assertions and cannot trigger PP5.
PP5: met only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; ordinary submissions, aggregate labels, non-expert assertions, and gene-level evidence do not qualify.
No applicable DNMT3A VCEP or gene-specific framework was available, so the generic ACMG/AMP population threshold applies. The highest observed gnomAD v4.1 population frequency is 8.474389547348956e-07 in the European (non-Finnish) population, and the combined frequency is 6.195134341488195e-07 (1/1,614,170 alleles), both far below the generic BA1 stand-alone threshold of >=0.05. The case contains no non-cancer subset result; no alternative source is mandated by a governing specification.
Generic ACMG/AMP BA1: allele frequency >=0.05; use the highest credible population frequency.
No applicable DNMT3A VCEP or gene-specific framework was available, so the supplied generic BS1 threshold applies. The highest observed gnomAD v4.1 population frequency is 8.474389547348956e-07 and the combined frequency is 6.195134341488195e-07, both far below the generic BS1 threshold of >=0.01. The case contains no non-cancer subset result; no alternative source is mandated by a governing specification.
Generic BS1: allele frequency >=0.01; use a credible population-frequency threshold when no gene-specific derivation exists.
No applicable DNMT3A VCEP or gene-specific framework was available. The available population data show one heterozygous allele and zero homozygotes in gnomAD v4.1, but do not document the carrier's age, phenotype, or disease status and therefore do not establish observation in a healthy adult. No qualifying healthy-adult homozygote or phenotype-confirmed healthy carrier observation is available for this variant, so BS2 is not met.
Generic BS2: observation of the variant in healthy adult individuals at a genotype relevant to the disease mechanism; population presence without phenotype/age documentation is insufficient.
The variant is a missense substitution, NM_022552.4:c.2106T>A (p.Asp702Glu), so BP4 is evaluated using the missense REVEL path only. REVEL is 0.936, which exceeds all supplied benign BP4 cutoffs (supporting <=0.29, moderate <=0.183, strong <=0.016); therefore BP4 is not met. The SpliceAI max delta of 0.017 is not considered because splice predictions cannot provide BP4 for a missense variant, and BayesDel has no generic ACMG strength calibration. No governing DNMT3A VCEP specification was available.
generic_acmg_revel_bp4
BP6 is restricted here to an exact-variant ClinVar expert-panel assertion of Benign or Likely benign. The exact variant NM_022552.4:c.2106T>A (NP_072046.2:p.Asp702Glu) was not found in ClinVar, with no variation ID, expert-panel review status, or expert-panel classification. Therefore BP6 is not met; absence from ClinVar is not itself an expert-panel benign assertion.
BP6: met only for an exact-variant ClinVar expert-panel Benign or Likely benign classification; ordinary submissions, aggregate labels, non-expert assertions, and absence from ClinVar do not qualify.
No proband-level de novo observation is documented for NM_022552.4:c.2106T>A (NP_072046.2:p.(Asp702Glu)); the available case evidence does not report parental genotypes, confirmed maternity and paternity, or testing methodology. Therefore PS2 cannot be assessed.
Generic ACMG/AMP PS2: confirmed de novo occurrence in the proband with confirmed maternity and paternity; no strength can be assigned without the required family testing evidence.
No DNMT3A-specific VCEP or gene-specific functional specification is available, so the generic ACMG/AMP framework applies. The only relevant retrieved functional paper (PMID:34429321) describes high-throughput methyltransferase and protein-stability assays across 253 patient-associated DNMT3A variants, but its extracted finding explicitly states that NM_022552.4:c.2106T>A (p.Asp702Glu) was not mentioned. Aggregate results that do not test or identify this variant do not establish a damaging effect for this variant, and no validated variant-specific assay result with appropriate controls was available to support PS3 at any strength.
No applicable DNMT3A VCEP or gene-specific framework was retrieved, so the generic ACMG/AMP PS4 concept applies: a case-control enrichment or adequately documented affected-case series for the exact variant is required. The available evidence contains no exact-variant case count, control count, odds ratio, likelihood ratio, p-value, or other validated enrichment statistic. Therefore PS4 cannot be assessed rather than inferred from gene-level cancer context or a non-variant-specific publication.
Generic PS4: apply only when the exact variant is significantly enriched in affected individuals or a validated case-control study supports disease association; no numeric threshold is available here.
No applicable DNMT3A-specific VCEP or gene framework was available, so the generic ACMG/AMP PM3 rule was used. PM3 requires the variant to be observed in trans with a pathogenic or likely pathogenic variant in an affected individual with a recessive disorder, with strength based on the number and quality of such observations. The available case materials contain no affected-proband observation, second pathogenic allele, phase determination, or inheritance data for NM_022552.4:c.2106T>A (NP_072046.2:p.(Asp702Glu)); therefore PM3 cannot be assessed.
generic_acmg_pm3: pathogenic_or_likely_pathogenic_variant_in_trans_in_affected_individual_with_recessive_disorder
PM5 was not assessed because no validated same-residue comparator set was available. The case artifact contains no candidate variants at DNMT3A residue 702 and explicitly warns that classic PM5 semantics could not be confirmed safely; therefore PM5 cannot be inferred from the absence of collected candidates.
Generic ACMG/AMP PM5: novel missense change at an amino-acid residue where a different missense change is established as pathogenic; comparator evidence is required.
No report of NM_022552.4:c.2106T>A as a presumed de novo variant is documented, and no parental testing, maternity/paternity confirmation, or proband phenotype documentation is available to support a less-than-complete de novo observation. Therefore PM6 cannot be assessed.
Generic ACMG/AMP PM6: presumed de novo occurrence without confirmation of maternity and paternity; apply only when a proband observation and appropriate de novo context are documented.
No affected relatives carrying NM_022552.4:c.2106T>A, unaffected relatives lacking the variant, informative meioses, or family-level phenotype and genotype data are documented. Consequently, there is no segregation series from which PP1 strength can be assigned.
Generic ACMG/AMP PP1: co-segregation with disease in multiple affected family members; strength depends on the number and informativeness of meioses and the quality of phenotype-genotype correlation.
PP2 was not assessed. The available evidence establishes that DNMT3A has functionally important missense variation, but it does not provide a validated gene-level estimate showing that missense variation is a common disease mechanism while benign missense variation is rare. The single functional profiling paper studied patient-associated variants and cannot by itself establish the PP2 gene-level prerequisite.
Generic ACMG/AMP PP2: missense is a common mechanism of disease in the gene and benign missense variation is uncommon; gene-level calibration is required.
No applicable DNMT3A VCEP or gene-specific framework was retrieved, so the generic ACMG/AMP PP4 concept applies: the patient's phenotype or family history must be highly specific for a disease associated with the gene. The available evidence does not document a patient phenotype, family history, or a disease-specific phenotypic match for this exact variant. Gene-level statements about DNMT3A and hematologic malignancy are not patient-specific and are insufficient for PP4.
Generic PP4: apply only when the patient's phenotype or family history is highly specific for a disease associated with the gene; no such patient-level evidence is available.
No DNMT3A-specific VCEP or gene-specific functional specification is available, so the generic ACMG/AMP framework applies. The available functional publication (PMID:34429321) reports aggregate methyltransferase-activity and protein-stability results for 253 DNMT3A variants, but the extracted finding confirms that NM_022552.4:c.2106T>A (p.Asp702Glu) was not mentioned. It therefore provides no variant-specific evidence of a normal or benign functional effect, and no validated benign assay result with appropriate controls and biologically relevant readout was available to support BS3 at any strength.
No phenotype-appropriate relatives who lack NM_022552.4:c.2106T>A are documented, and no family study establishes non-segregation with disease. The absence of family segregation data cannot be interpreted as evidence against causality; therefore BS4 is not assessed.
Generic ACMG/AMP BS4: lack of segregation in affected members of a family; apply only when informative affected relatives are tested and the phenotype assessment is appropriate.
BP1 was not assessed. The available material does not establish that DNMT3A-related disease is caused predominantly by truncating variants with missense variants generally benign. The functional literature instead demonstrates substantial functional impact among DNMT3A missense variants, but it does not provide the gene-level variant-spectrum analysis required to apply or exclude BP1 definitively.
Generic ACMG/AMP BP1: missense variant in a gene for which primarily truncating variants are known to cause disease; gene-level mechanism evidence is required.
No applicable DNMT3A-specific VCEP or gene framework was available, so the generic ACMG/AMP BP2 rule was used. BP2 requires observation of the variant in trans with a pathogenic or likely pathogenic variant in a disorder with a dominant inheritance pattern, or in cis with a pathogenic or likely pathogenic variant in any inheritance pattern. The available case materials contain no affected-proband observation, additional pathogenic allele, phase determination, or inheritance data for NM_022552.4:c.2106T>A (NP_072046.2:p.(Asp702Glu)); therefore BP2 cannot be assessed.
generic_acmg_bp2: pathogenic_or_likely_pathogenic_variant_in_trans_for_dominant_disorder_or_in_cis_for_any_disorder
No applicable DNMT3A VCEP or gene-specific BP5 rule was retrieved. The available evidence contains no alternative molecular diagnosis explaining the patient's phenotype, no documented competing pathogenic variant, and no BP5-specific likelihood-ratio-style statistic or governing threshold. Gene-level cancer context, population frequency, and absence from ClinVar do not establish BP5. Because the required alternative explanation is not documented, BP5 is not assessed.
BP5: requires a documented alternative molecular explanation for the phenotype; any numeric BP5 rule must use the operator and threshold stated for BP5 itself, not a direction borrowed from another criterion.
deterministic_prefilter: requires_null_variant_class
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
deterministic_prefilter: requires_repeat_region_indel
deterministic_prefilter: requires_synonymous
Every interpreted variant in DNMT3A, mapped onto the exon structure of NM_022552.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)1 / 1,180,026 | 8.5e-07 |
This variant is present in gnomAD v4.1 (AF= 6.19513e-07; MAF= 0.00006%, 1/1614170 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47439e-07; MAF= 0.00008%, 1/1180026 alleles, homozygotes = 0).
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
The variant is a missense substitution, NM_022552.4:c.2106T>A (p.Asp702Glu), so PP3 is evaluated using the missense REVEL path only. REVEL is 0.936, which meets the generic ClinGen SVI strong PP3 threshold of >=0.932 from the Pejaver et al. 2022 calibration (PMID:36413997). SpliceAI and BayesDel are not used for this criterion: SpliceAI is the non-missense path and BayesDel has no generic ACMG strength calibration. No governing DNMT3A VCEP specification was available.
generic_acmg_revel_pp3_strong
The variant is a missense substitution, NM_022552.4:c.2106T>A (p.Asp702Glu), so BP4 is evaluated using the missense REVEL path only. REVEL is 0.936, which exceeds all supplied benign BP4 cutoffs (supporting <=0.29, moderate <=0.183, strong <=0.016); therefore BP4 is not met. The SpliceAI max delta of 0.017 is not considered because splice predictions cannot provide BP4 for a missense variant, and BayesDel has no generic ACMG strength calibration. No governing DNMT3A VCEP specification was available.
generic_acmg_revel_bp4
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.936. BayesDel score = 0.415589.
1 paper record listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Across the protein, 74% (187 of 253) of the variants were classified as severe loss of function (LOF; Fig. 1E; Supplementary Figs. S1B–S1D, S2A, S3A, and S4A), with 85% (23 of 27) and 81% (114 of 140) of those in the PWWP and MTase domains, respectively, exhibiting little or no activity.
Location Results, “Methyltransferase Function of 253 Disease-Associated DNMT3A Variants”
Context High-throughput HOXA5-Snrpn-BFP methyltransferase reporter assay and DNMT3A-GFP/DsRed protein-stability assay applied to 253 patient-associated DNMT3A variants.
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= 6.19513e-07; MAF= 0.00006%, 1/1614170 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47439e-07; MAF= 0.00008%, 1/1180026 alleles, homozygotes = 0).
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
This variant is absent from ClinVar.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.936. BayesDel score = 0.415589.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. DNMT3A, a tumor suppressor and DNA methyltransferase, is recurrently mutated in acute myeloid leukemia and other hematologic malignancies.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.