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DNMT3Ac.2395C>TUncertain significance
Print report
Variant interpretation report

DNMT3A c.2395C>T, p.(Pro799Ser)

NM_022552.4:c.2395C>T NP_072046.2:p.(Pro799Ser) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About DNMT3A

No gene-level summary was recorded for this case.

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
PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 (0/0 alleles) and is present at an extremely low frequency in gnomAD v4.1 (4/1,613,986 alleles; AF=2.48e-6; 0.00025%; 0 homozygotes), with the highest subpopulation frequency in European (non-Finnish) at 4/1,179,910 alleles (AF=3.39e-6; 0.00034%). These allele frequencies are well below the 0.1% PM2 threshold for a rare variant absent from population controls.

PP3Supporting
PP3 · supporting

In silico prediction tools support a deleterious effect: REVEL score=0.916 (strongly pathogenic, threshold ≥0.9). BayesDel score=0.504 (borderline damaging, above the typical 0.27-0.50 range). SpliceAI predicts no splicing impact (max delta score=0.04), but this does not negate the protein-level prediction. The high REVEL score supports PP3 at supporting strength; the borderline BayesDel score precludes upgrading to moderate.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.040 maximum delta

Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement 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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV104391761, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

27 criteria with recorded statuses: 2 met · 7 not met · 15 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

This variant is a missense substitution (c.2395C>T, p.Pro799Ser) in exon 20 of DNMT3A (NM_022552.4). It is absent from ClinVar and has an extremely low allele frequency in gnomAD v4.1 (4/1,613,986 alleles; AF=0.00025%), meeting PM2 (supporting). In silico prediction tools support a deleterious effect (REVEL=0.916; BayesDel=0.504), meeting PP3 (supporting). SpliceAI predicts no significant splicing alteration (max delta=0.04).

No variant-specific functional data, de novo observations, case-control enrichment, segregation data, or clinical phenotype information are available for this variant. Two publications (PMID:24345752 and PMID:34429321) were identified as potentially relevant but neither could be verified to contain this exact variant (NM_022552.4:c.2395C>T/p.Pro799Ser). PVS1 does not apply to this missense variant. No same-residue comparator variants (PM5) were identified. The variant has been observed once in COSMIC (COSV104391761) as a somatic finding.

With PM2 (supporting) and PP3 (supporting) as the only met criteria, the evidence does not reach any classification threshold under the generic ACMG/AMP 2015 combination rules (PMID:25741868). Two supporting criteria alone are insufficient for Likely Pathogenic (requires ≥1 moderate + 4 supporting or stronger combinations). This variant is classified as a Variant of Uncertain Significance (VUS). Review of full-text PMID:34429321 (Huang et al., systematic DNMT3A variant profiling) is recommended, as it may contain functional data for Pro799Ser that could upgrade PS3/BS3 status.

Met · 2

PM2 SupportingThis variant is absent from gnomAD v2.1 (0/0 alleles) and is present at an extremely low frequency in gnomAD v4.1 (4/1,613,986 alleles; AF=2.48e-6; 0.00025%; 0 homozygotes), with the highest subpopulation frequency in European (non-Finnish) at 4/1,179,910 alleles (AF=3.39e-6; 0.00034%). These allele frequencies are well below the 0.1% PM2 threshold for a rare variant absent from population controls. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent (0 alleles)
  • gnomAD v4.1: AF=2.48e-6 (4/1
  • 613
  • 986 alleles
  • 0 homozygotes)
  • grpmax FAF=7.9e-7
Sources
gnomad_v2 ↗gnomad_v4 ↗
PP3 SupportingIn silico prediction tools support a deleterious effect: REVEL score=0.916 (strongly pathogenic, threshold ≥0.9). BayesDel score=0.504 (borderline damaging, above the typical 0.27-0.50 range). SpliceAI predicts no splicing impact (max delta score=0.04), but this does not negate the protein-level prediction. The high REVEL score supports PP3 at supporting strength; the borderline BayesDel score precludes upgrading to moderate. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.916 (deleterious)
  • BayesDel: 0.504 (borderline damaging)
  • SpliceAI max_delta: 0.04 (no splicing impact)
Sources
revelbayesdelspliceai ↗

Not met · 7 · evaluated, threshold not reached

PM1 This variant (p.Pro799Ser) does not lie within a statistically significant mutational hotspot in DNMT3A as assessed by CancerHotspots.org. Residue Pro799 is not identified as a significant hotspot residue. No well-established functional domain without benign variation has been demonstrated for this specific residue under generic ACMG criteria. Details ▾Hide ▴
Evidence considered
  • CancerHotspots.org: not a significant hotspot residue
  • residue Pro799 not enriched for somatic missense mutations above background
PP2 PP2 requires a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease, supported by a high missense Z-score or equivalent constraint metric. Although DNMT3A is a recognized disease gene (Tatton-Brown-Rahman syndrome), no gnomAD missense constraint metric (Z-score or observed/expected ratio) is available in the evidence packet to support PP2 application under generic ACMG criteria. Details ▾Hide ▴
Evidence considered
  • DNMT3A is a known disease gene but no missense constraint metrics provided in evidence packet to support PP2
Still missing
  • gnomAD missense constraint metrics not retrieved
BA1 The maximum allele frequency in gnomAD v4.1 is 0.00034% (European non-Finnish subpopulation), which is far below the 1% BA1 threshold. This variant is too rare in population databases to qualify as a benign stand-alone criterion. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 maximum subpopulation AF: 0.00034% (NFE)
  • well below 1% BA1 threshold
Sources
gnomad_v4 ↗
BS1 The maximum allele frequency in gnomAD v4.1 is 0.00034% (European non-Finnish), which is far below the 0.3% BS1 threshold. This variant is too rare in population databases to qualify as a benign strong criterion based on allele frequency. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 maximum subpopulation AF: 0.00034% (NFE)
  • well below 0.3% BS1 threshold
Sources
gnomad_v4 ↗
BP1 BP1 applies to missense variants in genes where a truncating mechanism is the primary cause of disease. Tatton-Brown-Rahman syndrome (DNMT3A-related disorder) is caused by both missense and truncating germline variants. Missense variants are a well-established disease mechanism in DNMT3A, so BP1 cannot be applied to this variant. Details ▾Hide ▴
Evidence considered
  • Tatton-Brown-Rahman syndrome is caused by both missense and loss-of-function DNMT3A variants
  • missense is a known disease mechanism
BP4 BP4 requires multiple lines of computational evidence to suggest no impact on the gene product. However, REVEL predicts a strongly deleterious effect (score=0.916) and BayesDel is borderline damaging (0.504). The combined in silico evidence suggests a damaging rather than benign effect, precluding application of BP4. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.916 (deleterious
  • contradicts BP4)
  • BayesDel: 0.504 (borderline damaging)
  • SpliceAI max_delta: 0.04 (no splicing impact but does not override protein-level predictions)
Sources
revelbayesdelspliceai ↗
BP7 BP7 applies only to synonymous (silent) variants with no predicted impact on splicing. This variant is a missense substitution (c.2395C>T, p.Pro799Ser) resulting in an amino acid change and therefore does not qualify. Details ▾Hide ▴
Evidence considered
  • Variant is missense (p.Pro799Ser)
  • not synonymous
  • BP7 not applicable to amino acid-changing variants

Not assessed · 15 · no assessment recorded

PS1 No alternative nucleotide change at codon 799 resulting in the same p.Pro799Ser amino acid change has been identified in ClinVar or the literature. This variant is absent from ClinVar entirely, and no comparably classified same-amino-acid-change variants are available for assessment. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no alternative nucleotide change at Pro799 leading to Ser identified in any database
Still missing
  • No ClinVar entries for same amino acid change from different nucleotide substitution
PS2 No de novo observation with confirmed maternity and paternity is available for this variant. The targeted exploratory literature search for PS2 evidence did not return any result. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified
  • exploratory search for PS2 returned no data
Still missing
  • No de novo observation data available
PS3 Two candidate publications (PMID:24345752 and PMID:34429321) were identified as potentially containing functional evidence for DNMT3A variants. However, full-text retrieval for both yielded only Sci-Hub boilerplate content rather than the actual articles. The abstract of PMID:24345752 does not mention DNMT3A or this variant. The abstract of PMID:34429321 discusses DNMT3A variant profiling generally but does not specifically mention p.Pro799Ser or c.2395C>T. Neither publication can be verified to contain variant-specific functional evidence for NM_022552.4:c.2395C>T. Details ▾Hide ▴
Evidence considered
  • PS3 exploratory search returned no usable variant-specific functional evidence
Still missing
  • PMID:34429321 may contain relevant DNMT3A functional profiling data but full-text could not be verified
  • reviewer should manually review this publication for P799S-specific data
Sources
2434575234429321
PS4 No case-control or cohort data demonstrating enrichment of this variant in affected individuals versus controls is available. The variant is absent from ClinVar with zero submitters. The exploratory search for PS4 evidence did not return any result. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no case-control enrichment data available
  • exploratory search returned no result
Still missing
  • No prevalence data in affected vs. control populations
PM6 No de novo observation without confirmation of paternity and maternity is available for this variant. The exploratory search for PM6 evidence did not return any result. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified
  • exploratory search returned no data
Still missing
  • No de novo observations reported
PP1 No co-segregation data with disease in multiple affected family members is available for this variant. The exploratory search for PP1 evidence did not return any result. Details ▾Hide ▴
Evidence considered
  • No family segregation studies identified
  • exploratory search returned no data
Still missing
  • No segregation data available
PP4 No proband phenotype or clinical history is available in the case data. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Without clinical information, this criterion cannot be assessed. Details ▾Hide ▴
Evidence considered
  • No proband clinical phenotype provided
Still missing
  • No proband phenotype information available
PP5 No reputable source has reported this variant as pathogenic. This variant is absent from ClinVar (zero submitters, zero classifications). No diagnostic laboratory or expert panel has issued a pathogenic assertion. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no pathogenic assertion from any reputable source
Still missing
  • No germline pathogenic classification by any submitter
BS2 No observation of this variant in a healthy adult individual with full penetrance expected at an early age is available. The exploratory search for BS2 evidence did not return any result. Details ▾Hide ▴
Evidence considered
  • No healthy adult carrier data available
  • exploratory search returned no data
Still missing
  • No data on healthy adult carriers
BS3 The same two publications flagged for PS3 (PMID:24345752, PMID:34429321) were considered for BS3. Full-text could not be verified for either publication. No variant-specific functional evidence demonstrating a benign effect is available. Details ▾Hide ▴
Evidence considered
  • No verified functional studies showing no damaging effect for this specific variant
Still missing
  • PMID:34429321 may contain functional data for DNMT3A variants
  • reviewer should assess for P799S-specific benign functional evidence
Sources
2434575234429321
BS4 No lack of segregation data is available for this variant in affected family members. The exploratory search for BS4 evidence did not return any result. Details ▾Hide ▴
Evidence considered
  • No segregation data available
  • exploratory search returned no data
Still missing
  • No family segregation data to demonstrate lack of segregation
BP2 No data on observations of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant for a recessive disorder, are available. Phase information is not present in the case evidence. Details ▾Hide ▴
Evidence considered
  • No phasing data or co-occurrence observations available
  • exploratory search returned no data
Still missing
  • No phase data with other pathogenic variants
BP5 BP5 requires an alternate molecular basis for disease in the proband that has been observed. No proband or alternative diagnosis data are available in the case evidence. Details ▾Hide ▴
Evidence considered
  • No proband data or alternative molecular diagnosis available
Still missing
  • No proband clinical or genetic data to assess alternative molecular basis
BP6 No reputable source has reported this variant as benign. This variant is absent from ClinVar with zero submitters. No diagnostic laboratory or expert panel has issued a benign classification. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no benign classification from any reputable source
Still missing
  • No germline benign classification by any submitter
PS5 No reputable source has recently reported this variant as pathogenic with unavailable supporting evidence. The variant has zero ClinVar submissions and no expert panel reviews. OncoKB classification of 'Likely Oncogenic' reflects somatic context and does not constitute a germline assertion by a reputable diagnostic source. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • OncoKB somatic 'Likely Oncogenic' classification does not meet PS5 germline requirements
Still missing
  • No germline pathogenic assertion from a reputable source
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.2395C>T, p.Pro799Ser) and does not fall into the default PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). PVS1 is not applicable to missense substitutions in the generic ACMG/AMP framework. Details ▾Hide ▴
Evidence considered
  • Missense variant (c.2395C>T) in exon 20
  • variant_bucket classified as 'other'
  • apply_generic_pvs1_framework=false per pvs1_variant_assessment.json
Sources
pvs1_generic_framework ↗
PM5 N/ANo same-residue comparator missense variants at codon 799 with established pathogenicity were identified. The pm5_candidates pipeline was unable to confirm classic same-residue PM5 semantics for this variant and recommends against application. Details ▾Hide ▴
Evidence considered
  • pm5_candidates.json: 0 same-residue candidates found
  • classic PM5 semantics could not be confirmed
BP3 N/ABP3 applies only to in-frame deletions or insertions in repetitive regions; this variant is a single-nucleotide missense substitution. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
DNMT3A
Transcript
NM_022552.4
Coding (HGVS c.)
NM_022552.4:c.2395C>T
Protein (HGVS p.)
NP_072046.2:p.(Pro799Ser)
GRCh38
chr2:25239143 G>A
GRCh37
chr2:25462012 G>A
COSMIC
COSV104391761

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…
gnomAD v4.1 4 / 1,613,986 alleles AF 2.48e-06 · 0 homozygotes · FAF 7.9e-07
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 2.5e-06 · 4 / 1,613,986 alleles · 0 hom · FAF 7.9e-07
European (non-Finnish)4 / 1,179,910 3.4e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.47834e-06; MAF= 0.00025%, 4/1613986 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.39009e-06; MAF= 0.00034%, 4/1179910 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +72 bp
0.000
SpliceAI acceptor gainat +370 bp
0.010
SpliceAI donor lossat -13 bp
0.010
SpliceAI donor gainat -3 bp
0.040
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.080

Other predictors

REVEL
0.916
BayesDel
0.505

How the predictions were used

PP3 SupportingIn silico prediction tools support a deleterious effect: REVEL score=0.916 (strongly pathogenic, threshold ≥0.9). BayesDel score=0.504 (borderline damaging, above the typical 0.27-0.50 range). SpliceAI predicts no splicing impact (max delta score=0.04), but this does not negate the protein-level prediction. The high REVEL score supports PP3 at supporting strength; the borderline BayesDel score precludes upgrading to moderate. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.916 (deleterious)
  • BayesDel: 0.504 (borderline damaging)
  • SpliceAI max_delta: 0.04 (no splicing impact)
Sources
revelbayesdelspliceai ↗
BP4 BP4 requires multiple lines of computational evidence to suggest no impact on the gene product. However, REVEL predicts a strongly deleterious effect (score=0.916) and BayesDel is borderline damaging (0.504). The combined in silico evidence suggests a damaging rather than benign effect, precluding application of BP4. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.916 (deleterious
  • contradicts BP4)
  • BayesDel: 0.504 (borderline damaging)
  • SpliceAI max_delta: 0.04 (no splicing impact but does not override protein-level predictions)
Sources
revelbayesdelspliceai ↗
BP7 BP7 applies only to synonymous (silent) variants with no predicted impact on splicing. This variant is a missense substitution (c.2395C>T, p.Pro799Ser) resulting in an amino acid change and therefore does not qualify. Details ▾Hide ▴
Evidence considered
  • Variant is missense (p.Pro799Ser)
  • not synonymous
  • BP7 not applicable to amino acid-changing variants

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.916. BayesDel score = 0.504786.

2 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

  • A targeted mutational landscape of angioimmunoblastic T-cell lymphoma.
    No paper-specific finding is recorded.
    PMID 24345752 ↗
  • Systematic Profiling of DNMT3A Variants Reveals Protein Instability Mediated by the DCAF8 E3 Ubiquitin Ligase Adaptor.
    No paper-specific finding is recorded.
    PMID 34429321 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 4 / 1,613,986 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.040 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

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= 2.47834e-06; MAF= 0.00025%, 4/1613986 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.39009e-06; MAF= 0.00034%, 4/1179910 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.916. BayesDel score = 0.504786.

Functional

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104391761, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.