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

PVS1 does not apply because p.Ser352Asn is a missense substitution rather than a null variant (nonsense, frameshift, or canonical splice site).

The variant is extremely rare in population databases (gnomAD v2.1 AF 0.00425% and v4.1 AF 0.00675%, no homozygotes), supporting PM2 at supporting strength.

Computational predictors are concordant for a benign effect (REVEL 0.098, BayesDel -0.52, SpliceAI max delta 0.29 below the high-confidence splice threshold), supporting BP4; PP3 is not met.

The variant has been observed as a somatic DNMT3A mutation in a therapy-related/secondary AML patient (PMID:21993668) and is curated as Likely Neutral by OncoKB; the somatic observation does not meet germline PS4, and no variant-specific functional data are available (PS3 not met; BS3 not met because no well-established functional studies exist).

ClinVar classifies the variant as Uncertain significance from two laboratories (1-star, single submitter), so PS5, PP5, and BP6 are not met.

No de novo, segregation, case-control, or phenotype-specific evidence is available, and no same-codon pathogenic comparator was identified, so PS2, PM6, PM5, PP1, and PP4 are not met.

Population allele frequencies are far below the BA1 (1%) and BS1 (0.3%) thresholds, so BA1 and BS1 are not met.

With only PM2 (supporting) and BP4 (supporting) met, no pathogenic or benign combination is reached under the generic ACMG/AMP 2015 rules, consistent with a classification of Uncertain Significance.

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 substitution (p.Ser352Asn, exon 9) and does not fall into the null-variant buckets (nonsense, frameshift, canonical +-1/2 splice) required for PVS1 under the ClinGen SVI PVS1 framework.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No pathogenic or likely pathogenic variant producing the same amino acid change (p.Ser352Asn) via a different nucleotide substitution was identified in ClinVar or the reviewed literature.	clinvar
PS2	Not met	No de novo occurrence of p.Ser352Asn with confirmed or assumed parentage was reported in the available evidence.
PS3	Not met	No variant-specific functional data exist for p.Ser352Asn. The variant is listed among novel somatic DNMT3A mutations in a t-AML/sAML cohort (PMID:21993668) without functional characterization; the systematic DNMT3A variant profiling study (PMID:34429321) does not include this variant in its available text; and OncoKB's Likely Neutral annotation is a curated label, not experimental evidence.	PMID:21993668 oncokb
PS4	Not met	No evidence of increased variant prevalence in affected individuals versus controls for germline disease. The variant has been observed once as a somatic mutation in therapy-related/secondary AML (PMID:21993668; COSMIC n=1), which does not constitute germline case evidence, and ClinVar reports the variant as Uncertain significance from two laboratories.	PMID:21993668 clinvar
PS5	Not met	No reputable source classifies p.Ser352Asn as pathogenic; ClinVar lists the variant as Uncertain significance with criteria provided by a single submitter.	clinvar
PM1	Not met	Residue Ser352 lies within the ADD (ATRX-DNMT3A-DNMT3L) domain of DNMT3A (approximately residues 280-430), a well-characterized functional domain; however, p.Ser352Asn is not a statistically significant mutational hotspot, OncoKB curates the substitution as Likely Neutral, and no variant-specific evidence demonstrates disruption of ADD-domain function, so domain-level PM1 is not met.	oncokb
PM2	Met	The variant is extremely rare in population databases: gnomAD v2.1 AF 0.00425% (12/282,532 alleles, 0 homozygotes, grpmax FAF 6.39e-05) and gnomAD v4.1 AF 0.00675% (109/1,614,124 alleles, 0 homozygotes, grpmax FAF 6.81e-05), both well below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic or likely pathogenic missense variant at the same codon (Ser352) with a different amino acid substitution was identified; the automated PM5 candidate search returned no comparators, and the S352D change observed in one somatic AML case (PMID:21993668) is not a germline pathogenic classification.	pm5_candidates PMID:21993668
PM6	Not met	No de novo observation, with or without confirmed parentage, was reported for p.Ser352Asn.
PP1	Not met	No cosegregation data in multiple affected family members are available for p.Ser352Asn.
PP2	Not met	Missense variants are a known mechanism of DNMT3A-related Tatton-Brown-Rahman syndrome, but no gene-specific missense constraint metric (e.g., gnomAD missense Z-score) or VCEP-defined PP2 threshold is available in the case materials to formally apply PP2.	pvs1_gene_context
PP3	Not met	In silico predictors are concordant for a benign effect - REVEL 0.098 (well below 0.5), BayesDel -0.5207 (negative, benign-leaning), and SpliceAI max delta 0.29 (below the 0.5 high-confidence splice-altering threshold, variant deep in exon 9) - so no computational evidence supports a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No proband phenotype data are available to establish a phenotype highly specific for DNMT3A-related disease.
PP5	Not met	ClinVar classifies p.Ser352Asn as Uncertain significance (2 laboratories; criteria provided, single submitter - 1 star), which does not meet the 3-star expert-panel threshold required for PP5, and the TBRS GeneReviews article (PMID:35771960) provides no variant-specific information in the available materials.	clinvar
BA1	Not met	The maximum allele frequency is 0.00675% (gnomAD v4.1), far below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	The highest subpopulation allele frequency is 0.01634% (South Asian, gnomAD v2.1), far below the 0.3% BS1 threshold.	gnomad_v2
BS2	Not met	The variant is present at very low frequency in gnomAD with no homozygotes, and no age- or phenotype-stratified healthy-adult cohort data demonstrate observation at a frequency consistent with a fully penetrant benign allele.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrate a lack of damaging effect for p.Ser352Asn. OncoKB's Likely Neutral annotation is a curated somatic oncogenicity label rather than experimental evidence, and in silico scores (REVEL 0.098, BayesDel -0.52) are predictive rather than functional.	oncokb revel bayesdel
BS4	Not met	No segregation data demonstrating absence of cosegregation with disease in affected families are available.
BP1	Not met	DNMT3A-related disease (Tatton-Brown-Rahman syndrome) is caused by both truncating and missense variants, so missense is a known disease mechanism and BP1 does not apply.	pvs1_gene_context
BP2	Not met	No observation of the variant in trans with a known pathogenic DNMT3A variant in an affected individual is available.
BP4	Met	Multiple computational predictors support no impact on protein function or splicing: REVEL 0.098 (well below 0.5), BayesDel -0.5207 (negative, benign-leaning), and SpliceAI max delta 0.29 (below the 0.5 high-confidence splice-altering threshold).	revel bayesdel spliceai
BP5	Not met	No alternate molecular basis of disease has been documented in a carrier of this variant.
BP6	Not met	ClinVar does not classify p.Ser352Asn as benign or likely benign by an expert panel (VUS, 1-star single submitter), so BP6 does not apply.	clinvar
BP7	N/A	BP7 applies to synonymous variants without predicted splice impact; c.1055G>A is a missense substitution (p.Ser352Asn).
BP3	N/A	BP3 applies only to in-frame insertions/deletions in repetitive regions; this is a substitution variant.
PM3	N/A	PM3 requires trans-phase observation with a pathogenic variant, which is not applicable for this autosomal-dominant context with no such data; skipped.
PM4	N/A	PM4 applies to protein-length-changing variants (in-frame indel or stop-loss); this is a substitution variant.

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