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 at very strong: c.1792C>T creates p.Arg598Ter in exon 15, 806 coding bases before the final exon, predicting nonsense-mediated decay.
Met at supporting strength: gnomAD v4.1 AF 2.85054e-05 is below the PM2 threshold of <=0.0001, with zero homozygotes.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PVS1 (very strong) plus PM2 (supporting) satisfy the generic ACMG/AMP fallback combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 46 / 1,613,732 alleles. Recorded AF 2.85054e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 2.39469e-05; MAF= 0.00239%, 6/250554 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.94629e-05; MAF= 0.00995%, 1/10054 alleles, homozygotes = 0); grpmax FAF= 7.04e-06.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.026. Refer to the recorded PP3/BP4 rationale for interpretation.
2 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: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV53039812, n = 17 times).
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: 2 met · 4 not met · 11 not assessed · 11 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; generic ACMG/AMP rules were used where applicable.
PS4, PP4, and BP5 remain not_assessed because the available evidence does not establish the required exact-variant prevalence, specific phenotype, or alternative molecular cause.
PP5 and BP6 are not_met because the exact-variant ClinVar record has zero expert-panel submissions.
No criteria match.
No DNMT3A-specific CSPEC/VCEP framework is available, so the ClinGen SVI generic PVS1 framework applies. DNMT3A loss of function is supported as a germline disease mechanism, making the gene-level PVS1 gate eligible. NM_022552.4 is the RefSeq-selected transcript and NM_022552.4:c.1792C>T is a nonsense variant producing NP_072046.2:p.(Arg598Ter) in exon 15. The stop occurs at coding position 1792, whereas the final exon begins at c.2598, placing the premature termination codon 806 coding bases before the terminal exon and well outside the terminal-exon/near-last-junction escape context; nonsense-mediated decay is therefore expected. The predicted protein is shortened from 913 to 598 residues, deleting 315 residues (34.5%), and the variant is not a canonical splice change. No evidence in the case data supports a non-critical distal exon or repeat-region exception, and no named SVI/VCEP downgrade rule applies. Therefore PVS1 is met at full generic strength.
ClinGen SVI generic PVS1 framework (PMC6185798): nonsense variant with established gene-level loss-of-function mechanism and predicted nonsense-mediated decay; no downgrade rule triggered.
No applicable DNMT3A-specific VCEP/CSPEC specification was available, so the supplied generic PM2 threshold was used. The variant is rare in population databases: gnomAD v4.1 AF 2.85054e-05 (46/1,613,732 alleles; 0 homozygotes; grpmax FAF 2.394e-05) and gnomAD v2.1 exome AF 2.39469e-05 (6/250,554 alleles; 0 homozygotes; grpmax FAF 7.04e-06). The maximum observed subpopulation AF, 3.37792e-05 in gnomAD v4.1 Ashkenazi Jewish individuals, remains below the supplied PM2 threshold of <=0.0001. These data support rarity, not complete absence, so PM2 is applied at supporting strength.
Generic PM2 supporting threshold: allele frequency <=0.0001; rarity is sufficient, but complete absence is not required.
PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. The exact ClinVar record for NM_022552.4:c.1792C>T (p.Arg598Ter) has three ordinary single-submitter clinical-laboratory submissions and zero expert-panel submissions. Its aggregate Pathogenic/Likely pathogenic label therefore does not satisfy PP5.
PP5 applies only when an exact-variant ClinVar expert panel classifies the variant as Pathogenic or Likely pathogenic; ordinary laboratory submissions and aggregate labels do not qualify.
No applicable DNMT3A-specific VCEP/CSPEC specification was available, so the supplied generic BA1 threshold was used. The variant is present at AF 2.85054e-05 in gnomAD v4.1 (46/1,613,732 alleles; 0 homozygotes) and AF 2.39469e-05 in gnomAD v2.1 exomes (6/250,554 alleles; 0 homozygotes), far below the generic BA1 stand-alone threshold of >=0.05 from ACMG/AMP 2015. The highest reported subpopulation AF is 3.37792e-05 in Ashkenazi Jewish individuals in gnomAD v4.1, also far below threshold.
Generic BA1 stand-alone threshold: allele frequency >=0.05; no applicable DNMT3A-specific framework was available.
No applicable DNMT3A-specific VCEP/CSPEC specification was available, so the supplied generic BS1 threshold was used. The variant's AF is 2.85054e-05 in gnomAD v4.1 and 2.39469e-05 in gnomAD v2.1 exomes, with the highest subpopulation AF 3.37792e-05 in Ashkenazi Jewish individuals; all are far below the generic BS1 threshold of >=0.01. The absence of homozygotes and the available ancestry-specific frequencies do not provide evidence for a disease-incompatible excess frequency.
Generic BS1 strong threshold: allele frequency >=0.01; no applicable DNMT3A-specific framework was available.
BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. The exact ClinVar record for NM_022552.4:c.1792C>T (p.Arg598Ter) has zero expert-panel submissions and no Benign or Likely benign expert-panel assertion. Its available laboratory submissions are Pathogenic or Likely pathogenic and are not eligible to trigger BP6.
BP6 applies only when an exact-variant ClinVar expert panel classifies the variant as Benign or Likely benign; ordinary laboratory submissions and aggregate labels do not qualify.
No evidence documents that DNMT3A NM_022552.4:c.1792C>T (p.Arg598Ter) was confirmed de novo in the proband by testing both biological parents. PMID:24614070 reports other de novo DNMT3A variants in an overgrowth cohort, but explicitly does not report this exact variant, so it cannot establish PS2 for this case.
Generic ACMG/AMP PS2 framework; no DNMT3A-specific VCEP/CSPEC specification was available.
No validated functional assay directly evaluating NM_022552.4:c.1792C>T (NP_072046.2:p.Arg598Ter) was identified. The reviewed literature reports DNMT3A truncating or other pathogenic variants in cohorts and discusses DNMT3A biology, but does not provide variant-specific experimental measurements, appropriate assay controls, or a calibrated functional result for p.Arg598Ter. The predicted premature stop and general loss-of-function mechanism are not themselves PS3 evidence.
No applicable DNMT3A VCEP or gene-specific framework was available, so generic ACMG/AMP PS4 was considered. The available literature extraction for PMID:24614070 describes an overgrowth cohort but explicitly does not mention NM_022552.4:c.1792C>T or p.Arg598Ter, and it provides no exact-variant case-control enrichment or variant-specific affected-case count. The available ClinVar record is composed of ordinary single-submitter laboratory assertions and is not case-control evidence. Therefore, PS4 cannot be adjudicated from the available evidence.
Generic PS4 requires a statistically significant excess of the exact variant in affected individuals compared with appropriate controls, or other validated variant-specific prevalence evidence; no applicable VCEP rule was available.
No evidence documents that this exact DNMT3A variant was presumed de novo without parental testing, nor does it provide a proband phenotype and technical context sufficient for PM6. PMID:24614070 reports other de novo DNMT3A variants and therefore cannot establish PM6 for this variant.
Generic ACMG/AMP PM6 framework; no DNMT3A-specific VCEP/CSPEC specification was available.
No affected or unaffected relatives, informative meioses, or family genotypes are documented for NM_022552.4:c.1792C>T (p.Arg598Ter). The available literature does not report this exact variant in a segregating family, so PP1 cannot be assessed.
Generic ACMG/AMP PP1 framework; no DNMT3A-specific VCEP/CSPEC specification was available.
No applicable DNMT3A VCEP or gene-specific framework was available, so generic ACMG/AMP PP4 was considered. The case materials identify the associated Tatton-Brown-Rahman overgrowth syndrome context, but they do not provide a documented phenotype for the individual carrying this exact variant that is sufficiently specific to the disorder. PMID:24614070 describes the general overgrowth phenotype spectrum and explicitly does not report this exact variant. Therefore, a highly specific phenotype match cannot be confirmed.
Generic PP4 requires the patient’s phenotype or family history to be highly specific for a disease with a single genetic etiology; no applicable VCEP rule was available.
The available gnomAD data show 0 homozygotes in both gnomAD v2.1 exomes and gnomAD v4.1, but do not establish that identified heterozygotes were healthy adult individuals assessed for Tatton-Brown-Rahman syndrome or that disease penetrance makes their presence benign evidence. The case contains no explicit healthy-adult observation, penetrance analysis, or disease-prevalence calibration sufficient to apply BS2. Therefore BS2 is not assessed rather than inferred from the absence of homozygotes or from another source's classification.
BS2 requires observation in healthy adult individuals in a disease context where the relevant penetrance and ascertainment support benign evidence; homozygote absence alone is insufficient here.
No validated functional assay demonstrated preserved function for NM_022552.4:c.1792C>T (NP_072046.2:p.Arg598Ter). The reviewed studies did not test this exact variant in a benign-function assay with suitable controls; cohort observations, predicted truncation, and absence of a reported assay result cannot establish BS3. Therefore no benign functional evidence or strength can be assigned.
No evidence documents a clinically informative unaffected relative who carries DNMT3A NM_022552.4:c.1792C>T (p.Arg598Ter), or any other non-segregation observation. The available literature does not provide exact-variant family data for BS4.
Generic ACMG/AMP BS4 framework; no DNMT3A-specific VCEP/CSPEC specification was available.
No DNMT3A-specific VCEP specification was available, so the generic ACMG/AMP framework was used. BP2 requires the evaluated variant to be observed in trans with a pathogenic variant in a disorder with a dominant inheritance pattern, or in cis with a pathogenic variant when the combination is shown to be benign or otherwise supports the BP2 context. The available case and literature evidence do not document an affected proband carrying NM_022552.4:c.1792C>T together with another pathogenic DNMT3A variant, do not provide parental or molecular phasing, and do not establish cis or trans placement with any pathogenic allele. ClinVar and population records do not provide phase or affected-proband allelic observations and cannot establish BP2.
BP2 requires documented cis or trans allelic context with a pathogenic variant, including phase and appropriate affected-proband or inheritance evidence; absence of such evidence is not itself evidence that BP2 is met or not met.
No applicable DNMT3A VCEP or gene-specific framework was available, so generic ACMG/AMP BP5 was considered. The available materials do not document a credible alternative molecular cause that independently explains the reported phenotype, nor do they provide a sufficiently detailed phenotype and diagnostic workup to evaluate this criterion. The presence of a general disease condition label or non-expert ClinVar assertion is not evidence for BP5.
Generic BP5 requires a well-established alternative molecular cause for the patient’s phenotype; no applicable VCEP rule was available.
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_missense
No DNMT3A-specific VCEP specification was available, so the generic ACMG/AMP framework was used. PM3 is intended for recessive disease and requires the evaluated variant to be observed in trans with a pathogenic variant in an affected individual, with phase and affected-proband evidence supporting biallelic disease. The available DNMT3A overgrowth study describes 13 different de novo DNMT3A mutations in 152 individuals, including the original proband-parent trio observations, which supports a dominant/de novo disease context rather than a recessive biallelic mechanism. No evidence establishes a recessive inheritance model for this DNMT3A disorder or provides a PM3-eligible affected individual with a pathogenic variant in trans.
PM3 is not applicable when the established disease context is dominant/de novo rather than recessive; PM3 requires affected-proband evidence demonstrating the evaluated variant in trans with a pathogenic variant.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_missense
PP3 is not applicable because NM_022552.4:c.1792C>T is a nonsense variant, producing NP_072046.2:p.(Arg598Ter), and this criterion is restricted to missense variants or intronic/splice-region variants assessed through the appropriate calibrated predictor path. No predictor score was evaluated for this out-of-scope criterion.
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_repeat_region_indel
BP4 is not applicable because NM_022552.4:c.1792C>T is a nonsense variant, producing NP_072046.2:p.(Arg598Ter), and this criterion is restricted to missense variants or intronic/splice-region variants assessed through the appropriate calibrated predictor path. No predictor score was evaluated for this out-of-scope criterion.
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 |
|---|
| Ashkenazi Jewish1 / 29,604 | 3.4e-05 |
| Admixed American2 / 60,020 | 3.3e-05 |
| South Asian3 / 91,080 | 3.3e-05 |
| European (non-Finnish)38 / 1,179,886 | 3.2e-05 |
| Remaining individuals1 / 62,478 | 1.6e-05 |
| African/African American1 / 75,024 | 1.3e-05 |
| Ashkenazi Jewish1 / 10,054 | 9.9e-05 |
| African/African American1 / 16,082 | 6.2e-05 |
| South Asian1 / 30,610 | 3.3e-05 |
| European (non-Finnish)3 / 113,196 | 2.7e-05 |
This variant is present in gnomAD v4.1 (AF= 2.85054e-05; MAF= 0.00285%, 46/1613732 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37792e-05; MAF= 0.00338%, 1/29604 alleles, homozygotes = 0); grpmax FAF= 2.394e-05.
This variant is present in gnomAD v2.1 (AF= 2.39469e-05; MAF= 0.00239%, 6/250554 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.94629e-05; MAF= 0.00995%, 1/10054 alleles, homozygotes = 0); grpmax FAF= 7.04e-06.
Not available in gnomAD-Canada v1.0.
PP3 is not applicable because NM_022552.4:c.1792C>T is a nonsense variant, producing NP_072046.2:p.(Arg598Ter), and this criterion is restricted to missense variants or intronic/splice-region variants assessed through the appropriate calibrated predictor path. No predictor score was evaluated for this out-of-scope criterion.
BP4 is not applicable because NM_022552.4:c.1792C>T is a nonsense variant, producing NP_072046.2:p.(Arg598Ter), and this criterion is restricted to missense variants or intronic/splice-region variants assessed through the appropriate calibrated predictor path. No predictor score was evaluated for this out-of-scope criterion.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). BayesDel score = 0.66.
5 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.
We identified an additional 11 de novo DNMT3A mutations. Thus in total, we found 13 different de novo DNMT3A mutations in 152 individuals with overgrowth phenotypes: 10 nonsynonymous mutations, two small frameshifting insertions and one inframe deletion (Figure 1, Table 1, Supplementary Figure 1).
Results, paragraphs 2-3; Figure 1 and Table 1
We also observed six frameshift, six nonsense, and three splice-site mutations and a 1.5-Mb deletion that included DNMT3A and eight other genes (Fig. 2 in the Supplementary Appendix).
Results, DNMT3A Mutations in AML
The remaining mutations were distributed throughout the gene and included 63 missense mutations, 37 mutations classified as truncations (12 nonsense, 13 frameshift, 12 at splice sites), and three in-frame deletions.
Results, DNMT3A Mutation Analysis; Outcome Stratified According to Type of DNMT3A Mutation
Certain types of variants (e.g. nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single exon or multi-exon deletion) can often be assumed to disrupt gene function by leading to complete absence of the gene product by lack of transcription or nonsense-mediated decay of an altered transcript. However, one must exercise caution in classifying these variants as pathogenic by considering the following principles:
Proposed Criteria for Interpretation of Sequence Variants, section "PVS1 Null 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= 2.85054e-05; MAF= 0.00285%, 46/1613732 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37792e-05; MAF= 0.00338%, 1/29604 alleles, homozygotes = 0); grpmax FAF= 2.394e-05.
This variant is present in gnomAD v2.1 (AF= 2.39469e-05; MAF= 0.00239%, 6/250554 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.94629e-05; MAF= 0.00995%, 1/10054 alleles, homozygotes = 0); grpmax FAF= 7.04e-06.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 1070654)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). BayesDel score = 0.66.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53039812, n = 17 times).
This variant does not lie in a statistically significant hotspot.