Variant classification summary

NM_022552.4:c.2106T>A

DNMT3A · NP_072046.2:p.(Asp702Glu) · NM_022552.4

GRCh37: chr2:25463576 A>T · GRCh38: chr2:25240707 A>T

Gene: DNMT3A Transcript: NM_022552.4

Final call

Likely Pathogenic

PM1 supporting PM2 supporting PP3 strong

Variant details

Gene

DNMT3A

Transcript

NM_022552.4

Protein

NP_072046.2:p.(Asp702Glu)

gnomAD AF

6.195134341488195e-07 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 supporting: Asp702 lies in DNMT3A's methyltransferase domain, where 81% of tested variants showed little or no activity.

2

PM2 supporting: gnomAD v4.1 shows one allele, zero homozygotes, and an allele frequency of 6.20e-7.

3

PP3 strong: REVEL 0.936 exceeds the calibrated strong threshold of 0.932.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion plus two supporting pathogenic criteria leads to Likely Pathogenic.

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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_022552.4:c.2106T>A in DNMT3A is a missense substitution predicted to produce NP_072046.2:p.(Asp702Glu). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no established pathogenic same-amino-acid change at DNMT3A Asp702 was identified, and the available functional paper does not mention Asp702Glu.	clinvar PMID:34429321
PS2	Not assessed	Not assessed: no documented de novo proband result or confirmed parental testing is available for this variant.
PS3	Not assessed	Not assessed: the assay study tested 253 DNMT3A variants but did not mention c.2106T>A (p.Asp702Glu).
PS4	Not assessed	Not assessed: no exact-variant case-control counts or validated enrichment statistic were available for PS4.
PM1	Met	Met, supporting: Asp702 lies in DNMT3A's MTase domain, where 81% of 140 tested variants showed little or no methyltransferase activity.	PMID:34429321
PM2	Met	Met at supporting strength: gnomAD v4.1 total AF is 6.20e-7, below the generic PM2 threshold of 0.0001, with one allele and zero homozygotes.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation, pathogenic second allele, phase, or inheritance data are available to establish PM3.	generic_acmg_combination_rules
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_022552.4:c.2106T>A in DNMT3A is a missense substitution predicted to produce NP_072046.2:p.(Asp702Glu). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no validated pathogenic or likely pathogenic alternate substitution at DNMT3A residue 702 was available for comparison.
PM6	Not assessed	Not assessed: no presumed de novo report or parental testing is documented for this variant.
PP1	Not assessed	Not assessed: no informative affected-relative segregation, meioses, or genotype-phenotype family data are documented.
PP2	Not assessed	Not assessed: available data show pathogenic missense biology but do not establish the required gene-level pattern of common disease-causing and rare benign missense variation.	PMID:34429321
PP3	Met	Met, strong: REVEL 0.936 meets the calibrated strong PP3 threshold of >=0.932 for this missense variant.	revel
PP4	Not assessed	Not assessed: no patient phenotype or disease-specific family history was documented to establish a highly specific DNMT3A match.
PP5	Not met	Not met: the exact variant has no ClinVar record or expert-panel Pathogenic/Likely pathogenic classification.	clinvar oncokb PMID:34429321
BA1	Not met	Not met: gnomAD v4.1 maximum population AF is 8.47e-7, far below the generic BA1 threshold of 0.05.	gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 maximum population AF is 8.47e-7, far below the generic BS1 threshold of 0.01.	gnomad_v4
BS2	Not met	Not met: gnomAD v4.1 shows 1 allele but 0 homozygotes and provides no phenotype-confirmed healthy-adult observation.	gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific benign functional result for c.2106T>A (p.Asp702Glu) was reported in the available assay study.
BS4	Not assessed	Not assessed: no informative affected relatives without the variant or demonstrated familial non-segregation is documented.
BP1	Not assessed	Not assessed: available DNMT3A data do not establish a predominantly truncating disease mechanism that would make missense variants generally benign.	PMID:34429321
BP2	Not assessed	Not assessed: no pathogenic partner allele, phase, affected-proband observation, or inheritance data are available to establish BP2.	generic_acmg_combination_rules
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_022552.4:c.2106T>A in DNMT3A is a missense substitution predicted to produce NP_072046.2:p.(Asp702Glu). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.936 exceeds the strongest benign BP4 cutoff of <=0.016 for this missense variant.	revel
BP5	Not assessed	Not assessed: no alternative molecular diagnosis or BP5-specific likelihood-ratio evidence was documented.
BP6	Not met	Not met: the exact variant has no ClinVar record or expert-panel Benign/Likely benign classification.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_022552.4:c.2106T>A in DNMT3A is a missense substitution predicted to produce NP_072046.2:p.(Asp702Glu). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.