Variant classification summary

NM_022552.4:c.1792C>T

DNMT3A · NP_072046.2:p.(Arg598Ter) · NM_022552.4

GRCh37: chr2:25467083 G>A · GRCh38: chr2:25244214 G>A

Gene: DNMT3A Transcript: NM_022552.4

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

DNMT3A

Transcript

NM_022552.4

Protein

NP_072046.2:p.(Arg598Ter)

gnomAD AF

2.850535280951236e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (very strong): the premature stop at p.Arg598Ter is predicted to trigger nonsense-mediated decay.

2

PM2 (supporting): the variant is rare in gnomAD, with AF 2.85054e-05 and zero homozygotes.

Final determination: Under the generic ACMG/AMP fallback, one very strong pathogenic criterion plus one supporting pathogenic criterion 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	Met	Met at very strong: c.1792C>T creates p.Arg598Ter in exon 15, 806 coding bases before the final exon, predicting nonsense-mediated decay.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_022552.4:c.1792C>T in DNMT3A is a nonsense substitution introducing a premature stop codon predicted to produce NP_072046.2:p.(Arg598Ter). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1'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
PS2	Not assessed	Not assessed: parental testing confirming this exact variant as de novo is not documented.	PMID:24614070
PS3	Not assessed	Not assessed: no validated assay provides a variant-specific functional measurement for DNMT3A p.Arg598Ter.
PS4	Not assessed	Not assessed: no exact-variant case-control enrichment or variant-specific affected-case count is available for PS4.
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_022552.4:c.1792C>T in DNMT3A is a nonsense substitution introducing a premature stop codon predicted to produce NP_072046.2:p.(Arg598Ter). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1'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
PM2	Met	Met at supporting strength: gnomAD v4.1 AF 2.85054e-05 is below the PM2 threshold of <=0.0001, with zero homozygotes.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	N/A	Not applicable: DNMT3A overgrowth cases are described as de novo in 13 individuals, indicating a dominant/de novo context rather than recessive biallelic disease.	PMID:24614070
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.1792C>T in DNMT3A is a nonsense substitution introducing a premature stop codon predicted to produce NP_072046.2:p.(Arg598Ter). 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	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_022552.4:c.1792C>T in DNMT3A is a nonsense substitution introducing a premature stop codon predicted to produce NP_072046.2:p.(Arg598Ter). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5'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
PM6	Not assessed	Not assessed: neither presumed de novo status nor supporting proband evidence is documented for this exact variant.	PMID:24614070
PP1	Not assessed	Not assessed: no informative family genotypes or cosegregation data are documented for this exact variant.	PMID:24614070
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_022552.4:c.1792C>T in DNMT3A is a nonsense substitution introducing a premature stop codon predicted to produce NP_072046.2:p.(Arg598Ter). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2'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
PP3	N/A	Not applicable: c.1792C>T is a nonsense variant, whereas PP3 is restricted to missense or intronic/splice-region variants.
PP4	Not assessed	Not assessed: the individual’s documented phenotype is insufficiently specific to confirm PP4 for this exact variant.
PP5	Not met	Not met: the exact ClinVar record has 0 expert-panel submissions, despite aggregate Pathogenic/Likely pathogenic laboratory labels.	clinvar
BA1	Not met	Not met: gnomAD v4.1 AF 2.85054e-05 is far below the generic BA1 threshold of >=0.05, with zero observed homozygotes.	gnomad_v4 gnomad_v2 PMID:25741868
BS1	Not met	Not met: the highest gnomAD v4.1 frequency is 3.37792e-05, far below the generic BS1 threshold of >=0.01.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: gnomAD shows zero homozygotes but does not establish healthy-adult status or sufficient penetrance evidence for BS2.	gnomad_v4 gnomad_v2 PMID:25741868
BS3	Not assessed	Not assessed: no validated controlled assay demonstrates preserved function for DNMT3A p.Arg598Ter.
BS4	Not assessed	Not assessed: no unaffected carrier or other exact-variant non-segregation evidence is documented.
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_022552.4:c.1792C>T in DNMT3A is a nonsense substitution introducing a premature stop codon predicted to produce NP_072046.2:p.(Arg598Ter). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1'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
BP2	Not assessed	Not assessed: no affected-proband second-variant or phase observation is documented for c.1792C>T.
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.1792C>T in DNMT3A is a nonsense substitution introducing a premature stop codon predicted to produce NP_072046.2:p.(Arg598Ter). 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	N/A	Not applicable: c.1792C>T is a nonsense variant, whereas BP4 is restricted to missense or intronic/splice-region variants.
BP5	Not assessed	Not assessed: no documented alternative molecular cause independently explaining the phenotype is available for BP5.
BP6	Not met	Not met: the exact ClinVar record has 0 expert-panel submissions and no Benign or Likely benign expert-panel 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.1792C>T in DNMT3A is a nonsense substitution introducing a premature stop codon predicted to produce NP_072046.2:p.(Arg598Ter). 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

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