NM_022552.4:c.1256del

DNMT3A · NP_072046.2:p.(Pro419LeufsTer232) · NM_022552.4

GRCh37: chr2:25469511 AG>A · GRCh38: chr2:25246642 AG>A

Gene: DNMT3A Transcript: NM_022552.4

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

DNMT3A

Transcript

NM_022552.4

Protein

NP_072046.2:p.(Pro419LeufsTer232)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_022552.4:c.1256del (p.Pro419LeufsTer232) is a frameshift deletion in exon 10 of DNMT3A, predicted to cause nonsense-mediated decay and complete loss of protein function. DNMT3A loss of function is an established mechanism for Tatton-Brown-Rahman syndrome (DNMT3A overgrowth syndrome), a germline disorder characterized by overgrowth, intellectual disability, and facial dysmorphism.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, supporting rarity in the general population.

No variant-specific functional studies, de novo reports, case-control data, or segregation analyses were identified in the reviewed literature for this specific variant. A single ClinVar submission from a clinical laboratory classifies the variant as Likely pathogenic for Tatton-Brown-Rahman overgrowth syndrome, but the evidence trail is limited to guideline citations without variant-specific published data.

Under generic ACMG/AMP 2015 criteria, the combination of PVS1 (very_strong) and PM2 (supporting) is insufficient to reach a Likely Pathogenic classification, which requires at minimum 1 Very Strong + 1 Moderate or 1 Strong + 1-2 Moderate or 2 Moderate + 2 Supporting criteria. The classification falls into Variant of Uncertain Significance (VUS), favoring pathogenic, pending additional clinical or functional evidence.

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	Met	NM_022552.4:c.1256del is a frameshift deletion in exon 10 of 23, predicted to introduce a premature termination codon at p.Pro419LeufsTer232 with consequent nonsense-mediated decay. DNMT3A loss of function is an established mechanism for Tatton-Brown-Rahman syndrome (DNMT3A overgrowth syndrome), a germline overgrowth disorder. Under ClinGen SVI PVS1 recommendations (PMC6185798), this frameshift variant meets PVS1 at full strength.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies when a variant produces the same amino acid change as a known pathogenic missense variant. NM_022552.4:c.1256del is a frameshift variant, not a missense substitution, and therefore PS1 is not applicable.
PS2	Not met	No de novo occurrence of NM_022552.4:c.1256del was identified in any reviewed publication. While de novo DNMT3A mutations are documented in Tatton-Brown-Rahman syndrome (PMID:24614070), this specific variant was not among the reported de novo events.
PS3	Not met	No variant-specific functional studies for NM_022552.4:c.1256del were identified in the reviewed literature. OncoKB curation suggests likely loss-of-function as a biological effect, but this is a curated inference rather than direct experimental evidence for this variant.
PS4	Not met	No case-control or prevalence data are available to demonstrate that this variant is significantly enriched in affected individuals compared with controls. The variant is absent from gnomAD population databases, but the number of independent proband observations is insufficient to meet PS4 thresholds.	gnomad_v2 gnomad_v4 gnomad_canada
PS5	Not met	A single ClinVar submission (SCV004805237, Clinical Genetics Laboratory, CHRU Nancy) classifies a matching variant as Likely pathogenic for Tatton-Brown-Rahman overgrowth syndrome, but this is a single-submitter record with no expert panel validation and the record is mapped to a different transcript version (NM_022552.5:c.1925del). Under generic ACMG, a single clinical laboratory submission without published evidence does not meet the PS5 threshold requiring a reputable source.	clinvar
PM1	Not met	NM_022552.4:c.1256del is located in exon 10, which lies between the PWWP domain (exons 8-9) and the ADD domain (exons 13-15) of DNMT3A. Cancer Hotspots analysis did not identify this position as a statistically significant mutational hotspot. No well-established critical functional domain has been specifically defined at this residue under generic ACMG criteria.
PM2	Met	NM_022552.4:c.1256del is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (HostSeq genomes). Under generic ACMG/AMP, absence from large population databases in a gene where LoF variants are not commonly observed in controls supports PM2 at supporting level.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	SKIP: trivially not applicable per adjudication instructions.
PM4	N/A	PM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. NM_022552.4:c.1256del is a frameshift deletion causing a premature termination codon (p.Pro419LeufsTer232), not an in-frame change. The protein-length-altering effect is captured by PVS1.
PM5	N/A	PM5 applies to a novel missense variant at an amino acid residue where a different pathogenic missense change has been documented. NM_022552.4:c.1256del is a frameshift variant, not a missense substitution. Automatic PM5 candidate harvesting was unable to identify same-residue missense comparators.
PM6	Not met	No assumed de novo report was identified for NM_022552.4:c.1256del in any reviewed publication. PM6 requires at least one report of the variant occurring de novo without confirmed paternity/maternity.
PP1	Not met	No cosegregation data are available for NM_022552.4:c.1256del in affected families. PP1 requires evidence of segregation with disease in multiple affected family members.
PP2	N/A	PP2 applies to missense variants in genes where missense variants are a common disease mechanism and benign missense variation is rare. DNMT3A disease is driven primarily by loss-of-function variants, and NM_022552.4:c.1256del is a frameshift variant, not a missense substitution.
PP3	Not met	SpliceAI predicts no significant splice impact (max delta score 0.03, well below the 0.2 threshold). REVEL and BayesDel are not applicable to non-SNV variants. HCI prior scores are not available for DNMT3A. No in silico tool provides evidence that an effect beyond what PVS1 already captures is present. Under PMC6185798 guidance, PP3 should not be stacked with PVS1 for the same predicted effect.	spliceai
PP4	Not met	No patient phenotype or family history data are available for individuals carrying NM_022552.4:c.1256del. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	PP5 requires a reputable source to have reported the variant as pathogenic with evidence not available for independent evaluation. While a ClinVar submission from CHRU Nancy classifies this variant as Likely pathogenic, the record is mapped to a different transcript version (NM_022552.5:c.1925del), and the evidence trail cites only the ACMG guidelines (PMID:25741868) without variant-specific published evidence. A single clinical laboratory submission without expert panel validation does not constitute a reputable source under PP5.	clinvar
BA1	Not met	NM_022552.4:c.1256del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, with an allele frequency of 0. The BA1 threshold of >5% is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	NM_022552.4:c.1256del is absent from all population databases. The BS1 threshold of >0.3% allele frequency (generic ACMG non-VCEP) is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No observations of NM_022552.4:c.1256del in healthy adults for a recessive condition or in trans with a pathogenic variant for a dominant condition are available.
BS3	Not met	No well-established functional studies demonstrating no damaging effect of NM_022552.4:c.1256del were identified. No variant-specific functional data of any kind are available for this variant.
BS4	Not met	No segregation data are available for NM_022552.4:c.1256del. BS4 requires lack of segregation in affected family members, which cannot be assessed without family studies.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. NM_022552.4:c.1256del is itself a truncating (frameshift) variant, not a missense variant.
BP2	Not met	No observation of NM_022552.4:c.1256del in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant is available.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions without known function. NM_022552.4:c.1256del is a frameshift variant, not an in-frame change.
BP4	Not met	SpliceAI predicts no significant splice impact (max delta 0.03). However, SpliceAI alone does not constitute 'multiple lines of computational evidence' suggesting no impact, and for frameshift variants the primary deleterious mechanism is protein truncation with NMD — an effect not assessed by in silico splicing or missense prediction tools. BP4 is therefore not met.	spliceai
BP5	Not met	No observation of NM_022552.4:c.1256del in an individual with an alternate molecular basis for disease has been reported.
BP6	Not met	No reputable source has reported NM_022552.4:c.1256del as benign. The only ClinVar record classifies it as Likely pathogenic.
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact and non-conserved nucleotide. NM_022552.4:c.1256del is a frameshift deletion, not a synonymous variant.

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