NM_022552.4:c.2395C>T

DNMT3A · NP_072046.2:p.(Pro799Ser) · NM_022552.4

GRCh37: chr2:25462012 G>A · GRCh38: chr2:25239143 G>A

Gene: DNMT3A Transcript: NM_022552.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

DNMT3A

Transcript

NM_022552.4

Protein

NP_072046.2:p.(Pro799Ser)

gnomAD AF

2.478336243313139e-06 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This 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.	pvs1_generic_framework
PS1	Not assessed	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.
PS2	Not assessed	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.
PS3	Not assessed	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.
PS4	Not assessed	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.
PS5	Not assessed	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.
PM1	Not met	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.
PM2	Met	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 gnomad_v4
PM5	N/A	No 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.
PM6	Not assessed	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.
PP1	Not assessed	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.
PP2	Not met	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.
PP3	Met	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 bayesdel spliceai
PP4	Not assessed	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.
PP5	Not assessed	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.
BA1	Not met	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.	gnomad_v4
BS1	Not met	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.	gnomad_v4
BS2	Not assessed	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.
BS3	Not assessed	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.
BS4	Not assessed	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.
BP1	Not met	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.
BP2	Not assessed	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.
BP3	N/A	BP3 applies only to in-frame deletions or insertions in repetitive regions; this variant is a single-nucleotide missense substitution.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not assessed	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.
BP6	Not assessed	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.
BP7	Not met	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.

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