Variant classification summary

NM_022552.5:c.2645G>A

DNMT3A · NP_072046.2:p.(Arg882His) · NM_022552.5

GRCh37: chr2:25457242 C>T · GRCh38: chr2:25234373 C>T

Gene: DNMT3A Transcript: NM_022552.5

Final call

Likely Pathogenic

PS3 strong PM1 moderate PM6 supporting PP3 supporting

Variant details

Gene

DNMT3A

Transcript

NM_022552.5

Protein

NP_072046.2:p.(Arg882His)

gnomAD AF

0.0002648167121051626 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS3 strong is supported by multiple exact-variant biochemical, cellular, and murine studies showing impaired DNMT3A function.

2

Likely Pathogenic: PM1 moderate is supported by the recurrent Arg882 catalytic-domain hotspot in DNMT3A.

3

Likely Pathogenic: PM6 supporting is supported by a reported de novo occurrence without confirmed maternity and paternity.

4

Likely Pathogenic: PP3 supporting is supported by missense REVEL 0.742 meeting the supplied PP3 threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, 1 strong plus 1 moderate and 2 supporting pathogenic criteria supports Likely Pathogenic, provided no benign rule is also satisfied.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: a pathogenic alternate-nucleotide change producing DNMT3A p.Arg882His was not established in the reviewed evidence.	PMID:21067377 PMID:24656771
PS2	Not met	Not met: a de novo report exists, but confirmation of both maternity and paternity is not documented as required for PS2.	clinvar
PS3	Met	Met, strong: exact p.Arg882His showed reduced methyltransferase activity, greater than 80% inhibition in mixed complexes, impaired processivity, and concordant cellular and murine effects.	PMID:24656771 PMID:21067377 PMID:22722925 PMID:27841873 PMID:24167195
PS4	Not met	Not met: PMID:21067377 reports 27/281 AML tumors with R882H but no control count, OR/RR, or confidence interval meeting OR >5.0 and CI excluding 1.0.	PMID:21067377 gnomad_v4
PM1	Met	Met, moderate: Arg882 is a recurrent DNMT3A AML hotspot within the catalytic domain, with R882H the most frequent reported substitution.	PMID:21067377 PMID:24656771 PMID:22722925
PM2	Not met	Not met: gnomAD v4.1 AF is 0.000264817, exceeding the supplied PM2 threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the documented DNMT3A disorder context is heterozygous and de novo, not a recessive disorder requiring a pathogenic variant in trans.	clinvar
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: R882C, R882P, and R882S are reported, but their pathogenic determinations are not established in the supplied evidence.	PMID:21067377
PM6	Met	Met: the exact variant is reported de novo in an affected individual, but maternity and paternity confirmation is unavailable.	clinvar
PP1	Not assessed	Not assessed: no multiple affected relatives with matching genotypes and phenotypes are documented for segregation analysis.
PP2	Not assessed	Not assessed: gene-wide benign-missense constraint and a common missense disease mechanism are not both established by the supplied evidence.
PP3	Met	Met at supporting strength: missense REVEL 0.742 meets the generic PP3 threshold of >=0.644 but is below the moderate threshold of >=0.773.	revel
PP4	Not assessed	Not assessed: the case lacks sufficient index-patient phenotype and family-history detail to establish a highly specific single-etiology disorder presentation.
PP5	Not met	Not met: ClinVar has 0 exact-variant expert-panel submissions, and the relevant published evidence is available for independent evaluation.	clinvar
BA1	Not met	Not met: the highest observed gnomAD subpopulation AF is 0.000552043, far below the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest observed gnomAD subpopulation AF is 0.000552043, below the supplied generic BS1 default of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 0 homozygotes but provides no verified healthy-adult phenotype or age for a carrier.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: multiple exact-variant studies demonstrate reduced methyltransferase activity and impaired DNA methylation rather than no damaging effect on DNMT3A function or splicing.	PMID:24656771 PMID:21067377 PMID:22722925 PMID:27841873 PMID:24167195
BS4	Not assessed	Not assessed: no affected relatives without the variant are documented, so non-segregation cannot be evaluated.
BP1	Not assessed	Not assessed: the supplied evidence does not establish that DNMT3A disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no second pathogenic variant or phase result is documented for this heterozygous variant, so neither trans nor cis BP2 evidence can be established.	clinvar
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL 0.742 is above the <=0.29 BP4 supporting threshold, and the SpliceAI score is not applicable to this missense path.	revel
BP5	Not assessed	Not assessed: no documented alternate molecular diagnosis is available for the case in which DNMT3A p.Arg882His was found.	PMID:21067377
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign assertion exists; available exact-variant assertions are pathogenic or likely pathogenic.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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