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).1 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.2 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.3
DNMT3A
Final classification
VUS
DNMT3A c.2395C>T · p.Pro799Ser
DNMT3A
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).
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.
Classification rationale
PM2PP3
VUS
DNMT3A c.2395C>T
PM2 + PP3
→
VUS
1
gnomad_v2 ↗gnomad_v4 ↗revelbayesdelspliceai ↗
3
generic_acmg_combination_rules
Gene diagram
· NM_022552.4 · variants mapped to exon structure
DNMT3A
NM_022552.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
gnomAD v2.1: absent (0 alleles)gnomAD v4.1: AF=2.48e-6 (4/1613
✓
PP3
supporting
Pathogenic
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.
REVEL: 0.916 (deleterious)BayesDel: 0.504 (borderline damaging)SpliceAI max_delta: 0.04 (no splicing impact)
Assessed · not applied
Pathogenic
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.
PS2
No de novo observation with confirmed maternity and paternity is available for this variant.
PS3
Two candidate publications (PMID:24345752 and PMID:34429321) were identified as potentially containing functional evidence for DNMT3A variants.
PS4
No case-control or cohort data demonstrating enrichment of this variant in affected individuals versus controls is available.
PM1
This variant (p.Pro799Ser) does not lie within a statistically significant mutational hotspot in DNMT3A as assessed by CancerHotspots.org.
PM6
No de novo observation without confirmation of paternity and maternity is available for this variant.
PP1
No co-segregation data with disease in multiple affected family members is available for this variant.
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.
PP4
No proband phenotype or clinical history is available in the case data.
PP5
No reputable source has reported this variant as pathogenic.
Benign
BA1
The maximum allele frequency in gnomAD v4.1 is 0.00034% (European non-Finnish subpopulation), which is far below the 1% BA1 threshold.
BS1
The maximum allele frequency in gnomAD v4.1 is 0.00034% (European non-Finnish), which is far below the 0.3% BS1 threshold.
BS2
No observation of this variant in a healthy adult individual with full penetrance expected at an early age is available.
BS3
The same two publications flagged for PS3 (PMID:24345752, PMID:34429321) were considered for BS3.
BS4
No lack of segregation data is available for this variant in affected family members.
BP1
BP1 applies to missense variants in genes where a truncating mechanism is the primary cause of disease.
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.
BP4
BP4 requires multiple lines of computational evidence to suggest no impact on the gene product.
BP5
BP5 requires an alternate molecular basis for disease in the proband that has been observed.
BP6
No reputable source has reported this variant as benign.
BP7
BP7 applies only to synonymous (silent) variants with no predicted impact on splicing.
N/A · 3
PVS1 · PM5 · BP3
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00025%
· 4 / 1,613,986
0 hom · FAF 7.9e-05%
0 hom · FAF 7.9e-05%
European (non-Finnish) 4 / 1,179,910 |
0.00034% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Likely Oncogenic
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104391761, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 2 PMIDs not cited in assessment
34429321 ↗
Systematic Profiling of DNMT3A Variants Reveals Protein Instability Mediated by the DCAF8 E3 Ubiquitin Ligase Adaptor.
ONCOKB