NM_022552.4:c.1055G>A

DNMT3A · NP_072046.2:p.(Ser352Asn) · NM_022552.4

GRCh37: chr2:25469987 C>T · GRCh38: chr2:25247118 C>T

Gene: DNMT3A Transcript: NM_022552.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

DNMT3A

Transcript

NM_022552.4

Protein

NP_072046.2:p.(Ser352Asn)

gnomAD AF

6.752888873469449e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Neutral

Classification rationale

Interpretation summary

Generated evidence synthesis

This variant is present at very low frequency in gnomAD (AF 0.004-0.007%), meeting PM2 at supporting strength.

Multiple in silico predictors (REVEL 0.098, BayesDel -0.52, SpliceAI max delta 0.29) predict a benign effect, meeting BP4 at supporting strength.

The variant is a missense change not predicted to alter splicing; it does not qualify for PVS1, and no functional, segregation, or case-control data support a pathogenic role.

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and insufficient to classify this variant as either pathogenic or benign. The variant is classified as a variant of uncertain significance (VUS).

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	NM_022552.4:c.1055G>A is a missense variant (p.Ser352Asn) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not met	No pathogenic or likely pathogenic variant resulting in the same amino acid change (p.Ser352Asn) was identified from a different nucleotide change in ClinVar or the literature.	clinvar
PS2	Not met	No de novo observation with confirmed maternity and paternity was identified for this variant in the available evidence.
PS3	Not met	No variant-specific functional data are available for p.Ser352Asn. The variant is listed among novel somatic DNMT3A mutations in one AML cohort (PMID:21993668), but no functional characterization was performed. The systematic profiling study of DNMT3A variants (PMID:34429321) does not include this variant.	PMID:21993668 PMID:34429321
PS4	Not met	No variant-specific case-control prevalence data are available. The variant is reported in ClinVar as uncertain significance by two clinical laboratories, and no enriched observation in affected individuals has been demonstrated.	clinvar
PS5	Not met	No reputable source, including ClinVar, classifies this variant as pathogenic. ClinVar reports uncertain significance with criteria provided by a single submitter.	clinvar
PM1	Not met	Residue 352 lies within the PWWP domain of DNMT3A (approximately residues 278-427), but cancerhotspots.org does not identify this position as a statistically significant mutational hotspot, and no domain-level mutational enrichment specific to germline disease has been demonstrated for this region in the available evidence.
PM2	Met	This variant is present at very low frequency in population databases: gnomAD v2.1 allele frequency 4.25e-05 (0.00425%, 12/282,532 alleles, 0 homozygotes) and gnomAD v4.1 allele frequency 6.75e-05 (0.00675%, 109/1,614,124 alleles, 0 homozygotes), both well below the 0.1% threshold for PM2 supporting.	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic or likely pathogenic missense variant at the same codon (Ser352) with a different amino acid change was identified. The automated PM5 candidate search returned no eligible comparators.	pm5_candidates
PM6	Not met	No de novo observation, confirmed or unconfirmed, was identified for this variant in the available evidence.
PP1	Not met	No cosegregation data with disease in multiple affected family members is available for this variant.
PP2	Not met	Although DNMT3A is associated with Tatton-Brown-Rahman syndrome where missense variants are a known mechanism, no gene-specific missense constraint metric (e.g., missense Z-score) or VCEP-defined PP2 threshold is available to formally apply this criterion.
PP3	Not met	Multiple in silico predictors suggest a benign effect: REVEL score 0.098 (well below 0.5 threshold), BayesDel score -0.520724 (negative, supports benign), and SpliceAI max delta 0.29 (below 0.5 threshold for splice-altering prediction). No computational evidence supports a damaging effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical data are available to assess whether the phenotype is highly specific for DNMT3A-related disease.
PP5	Not met	ClinVar classification is uncertain significance with review status 'criteria provided, single submitter,' which does not meet the 3-star expert panel threshold required for PP5 application. The TBRS GeneReviews article (PMID:35771960) could not be confirmed to mention this specific variant as full text is unavailable.	clinvar PMID:35771960
BA1	Not met	This variant has a maximum allele frequency of 0.00675% in gnomAD v4.1, far below the 1% threshold for BA1.	gnomad_v4
BS1	Not met	This variant has a maximum allele frequency of 0.01634% in the South Asian population (gnomAD v2.1), far below the 0.3% threshold for BS1.	gnomad_v2
BS2	Not met	No specific observation of this variant in healthy adults at significant frequency, independent of disease penetrance, is available. While 12-109 alleles are observed in gnomAD, no age- or phenotype-stratified control data exist.
BS3	Not met	No well-established functional studies demonstrate a lack of damaging effect for this variant. While OncoKB classifies it as Likely Neutral, this is a curated somatic cancer label rather than direct experimental functional evidence. In silico predictors (REVEL 0.098, BayesDel -0.52) are suggestive of benign effect but do not constitute well-established functional studies per BS3 requirements.	oncokb revel bayesdel
BS4	Not met	No segregation data in affected families demonstrating lack of cosegregation with disease is available.
BP1	Not met	DNMT3A is associated with Tatton-Brown-Rahman syndrome, where both missense and truncating pathogenic variants are described. Missense variants are a known mechanism of disease in this gene; therefore BP1 does not apply.
BP2	Not met	No observation of this variant in trans with a known pathogenic DNMT3A variant is available.
BP4	Met	Multiple lines of computational evidence suggest this variant does not impact protein function or splicing: REVEL score 0.098 (well below 0.5, predicts benign), BayesDel score -0.520724 (negative, predicts benign), and SpliceAI max delta score 0.29 (below 0.5 threshold, no predicted splice-altering effect).	revel bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease is available.
BP6	Not met	ClinVar classification is uncertain significance, not benign or likely benign, and does not meet the 3-star expert panel threshold required for BP6 application.	clinvar
BP7	N/A	This variant is a missense change (c.1055G>A, p.Ser352Asn), not a synonymous variant. BP7 applies only to synonymous variants without predicted splice impact.
BP3	N/A	This is a substitution variant, not an in-frame insertion/deletion. BP3 applies only to in-frame indels in repetitive regions.
PM3	N/A	No observation in trans with a pathogenic variant is available, and PM3 requires specific trans-phase data.
PM4	N/A	This is a substitution variant, not a protein-length-changing variant (in-frame deletion/insertion or stop-loss). PM4 does not apply.

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