Variant classification summary

NM_022552.4:c.1154delC

DNMT3A · NP_072046.2:p.(Pro385ArgfsTer22) · NM_022552.4

GRCh37: chr2:25469613 CG>C · GRCh38: chr2:25246744 CG>C

Gene: DNMT3A Transcript: NM_022552.4

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

DNMT3A

Transcript

NM_022552.4

Protein

NP_072046.2:p.(Pro385ArgfsTer22)

gnomAD AF

3.7182415691970954e-06 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (very strong): NM_022552.4:c.1154delC is a frameshift deletion introducing a premature termination codon at position 406 (NP_072046.2:p.Pro385ArgfsTer22) in exon 10 of 22 coding exons, predicted to trigger nonsense-mediated decay. DNMT3A loss of function is an established disease mechanism for Tatton-Brown-Rahman syndrome, with a ClinGen haploinsufficiency score of 3.

2

PM2 (moderate): The variant is absent from gnomAD v2.1 (0/250,600 alleles) and present at extremely low frequency in gnomAD v4.1 (6/1,613,666 alleles; AF=3.72e-06). The highest subpopulation frequency is 1.67e-05 in the Admixed American population, well below the 0.1% PM2 threshold.

3

Combined classification: One very strong criterion (PVS1) and one moderate criterion (PM2) satisfy the Likely Pathogenic threshold under generic ACMG/AMP 2015 rules (1 Very Strong + 1 Moderate).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	NM_022552.4:c.1154delC is a frameshift deletion predicted to produce a premature termination codon at residue 406 (NP_072046.2:p.Pro385ArgfsTer22) in exon 10 of 22 coding exons. The variant is predicted to trigger nonsense-mediated decay. DNMT3A loss of function is an established disease mechanism for Tatton-Brown-Rahman syndrome (ClinGen haploinsufficiency score=3). Under ClinGen SVI PVS1 recommendations (PMC6185798), a null variant in a gene where LOF is a known mechanism qualifies for PVS1 at very strong level.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to nucleotide substitutions where a different change at the same position has been established as pathogenic. This variant is a single-nucleotide deletion, not a substitution.
PS2	Not met	PS2 requires a de novo occurrence with confirmed paternity and maternity. No de novo reports were identified for NM_022552.4:c.1154delC in ClinVar or the reviewed literature.	clinvar
PS3	Not assessed	PS3 requires well-established in vitro or in vivo functional studies demonstrating a damaging effect specific to this variant. OncoKB annotates this variant as Likely Loss-of-function in a somatic/oncogenic context, but no germline functional studies confirming a damaging effect for NM_022552.4:c.1154delC were identified. The variant type (frameshift with predicted NMD) already supports a null effect captured by PVS1; applying PS3 would constitute double-counting of the same evidence.	oncokb
PS4	Not met	PS4 requires a statistically significant enrichment of the variant in affected individuals compared with controls. No case-control studies or multiple unrelated probands with this variant were identified. The variant is absent from ClinVar and not reported in the reviewed literature.	gnomad_v2 gnomad_v4 clinvar
PS5	N/A	PS5 applies to novel missense variants at a residue where a different pathogenic missense change has been reported. This variant is a frameshift deletion, not a missense variant.
PM1	Not met	PM1 requires location in a mutational hot spot or critical functional domain without benign variation. The variant lies at residue 385 within the PWWP domain of DNMT3A, which is a functionally important region. However, Cancer Hotspots analysis did not identify a statistically significant mutational hotspot at this residue. Without a VCEP-specific domain specification for DNMT3A, PM1 cannot be confidently applied under generic ACMG.
PM2	Met	NM_022552.4:c.1154delC is absent from gnomAD v2.1 (0/250,600 alleles) and present at extremely low frequency in gnomAD v4.1 (6/1,613,666 alleles, AF=3.72e-06). Complete absence from the v2.1 dataset and near-absence from v4.1 satisfies PM2 under generic ACMG guidelines at moderate strength.	gnomad_v2 gnomad_v4
PM4	N/A	PM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. This variant is a frameshift deletion, which is assessed under PVS1 rather than PM4.
PM5	N/A	PM5 applies to novel missense variants at the same residue as a known pathogenic missense change. This variant is a frameshift deletion, not a missense. Automated PM5 candidate harvesting confirmed ineligibility.	pm5_candidates
PM6	Not met	PM6 requires an assumed de novo occurrence without confirmation of paternity and maternity. No such reports were identified for NM_022552.4:c.1154delC in ClinVar or the reviewed literature.	clinvar
PP1	Not met	PP1 requires cosegregation of the variant with disease in multiple affected family members. No family segregation data were identified for NM_022552.4:c.1154delC.
PP2	N/A	PP2 applies specifically to missense variants in genes with a low rate of benign missense variation where missense is a common disease mechanism. This variant is a frameshift deletion.
PP3	N/A	PP3 applies to in silico prediction evidence for missense and splice variants. This is a frameshift deletion. SpliceAI predicts no significant splice impact (max delta=0.05), and REVEL/BayesDel are not applicable to non-SNV variants. The deleterious effect of a frameshift is already captured by PVS1; applying PP3 would constitute double-counting.	spliceai
PP4	Not assessed	PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. No patient phenotype data were provided for this case.
PP5	Not assessed	PP5 requires that a reputable source recently reports the variant as pathogenic but the evidence is not independently verifiable. No such source was identified. The variant is absent from ClinVar.	clinvar
BA1	Not met	BA1 requires an allele frequency >1% in any general population. The highest observed frequency for NM_022552.4:c.1154delC is 1.67e-05 (0.00167%) in the Admixed American subpopulation of gnomAD v4.1, well below the 1% threshold.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires an allele frequency greater than expected for the disorder. The highest observed population frequency is 1.67e-05 (0.00167%), well below the 0.3% threshold. Tatton-Brown-Rahman syndrome is a rare disorder; this frequency is consistent with a rare pathogenic variant.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation of the variant in a healthy adult individual for a disorder with full penetrance expected at an early age. No such observations were identified for NM_022552.4:c.1154delC.
BS3	Not met	BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. OncoKB annotation indicates a Likely Loss-of-function effect for this variant, which is inconsistent with a benign functional assessment. No studies demonstrating a neutral functional effect were identified.	oncokb
BS4	Not met	BS4 requires lack of segregation of the variant with disease in affected family members. No family segregation data were identified for this variant.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This variant is itself a truncating (frameshift) variant.
BP2	Not met	BP2 requires observation of the variant in trans with a known pathogenic variant in a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern. No such observations were identified for NM_022552.4:c.1154delC.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions without known function. This variant is a frameshift deletion, not an in-frame change.
BP4	N/A	BP4 applies to computational evidence suggesting no impact on the gene product for missense and splice variants. This is a frameshift truncating variant. SpliceAI shows no splice effect (max delta=0.05), but the protein-level impact of a frameshift is assessed under PVS1. Applying BP4 would be inappropriate for a null variant.	spliceai
BP5	Not assessed	BP5 requires that the variant is found in a case with an alternate molecular basis for disease. No such data were available for assessment.
BP6	Not assessed	BP6 requires that a reputable source reports the variant as benign but the evidence is not independently verifiable. No such source was identified. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted impact on splicing. This variant is a frameshift deletion, not a synonymous variant.

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