NM_022552.4:c.1555-13C>A

DNMT3A · NP_072046.2:p.? · NM_022552.4

GRCh37: chr2:25467534 G>T · GRCh38: chr2:25244665 G>T

Gene: DNMT3A Transcript: NM_022552.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

DNMT3A

Transcript

NM_022552.4

Protein

NP_072046.2:p.?

gnomAD AF

3.1011136719418676e-06 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_022552.4:c.1555-13C>A is an intronic variant in DNMT3A located 13bp upstream of exon 14. It is extremely rare in population databases (PM2_Supporting: 5/1,612,324 alleles in gnomAD v4.1, AF=0.00031%; absent in gnomAD v2.1).

Multiple in silico splice prediction tools support a deleterious effect on splicing (PP3: SpliceAI DS_AG=0.98, Pangolin SG=0.79), predicting creation of a cryptic splice acceptor site that could lead to aberrant splicing.

This variant does not meet PVS1 criteria as it falls outside the canonical ±1,2 splice consensus and no RNA studies confirming aberrant splicing are available.

The variant is absent from ClinVar and no publications specifically reporting this variant were identified. No functional, segregation, de novo, or case-control data are available.

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	Not met	c.1555-13C>A is an intronic variant located 13bp upstream of exon 14, outside the canonical splice consensus (±1,2). Under ClinGen SVI PVS1 recommendations (PMC6185798), PVS1 is restricted to null variants (nonsense, frameshift, canonical ±1,2 splice, initiation codon, exon deletion). Non-canonical splice variants require RNA confirmation of aberrant splicing; no RNA studies are available. SpliceAI predicts cryptic acceptor gain (DS_AG=0.98) but computational prediction alone is insufficient to meet PVS1.	pvs1_generic_framework pvs1_variant_assessment pvs1_gene_context spliceai
PS1	Not met	No known pathogenic variant has been reported at this same nucleotide position (c.1555-13) to support PS1. The variant is absent from ClinVar and no publications identify a different pathogenic change at this locus.	clinvar
PS2	Not met	No de novo data (with confirmed maternity and paternity) is available for this variant.
PS3	Not met	No experimental functional studies (in vitro or in vivo) have been identified for this variant. PS3 requires well-established functional data demonstrating a damaging effect; SpliceAI in silico prediction alone does not satisfy this requirement.	spliceai
PS4	Not met	No case-control data demonstrating significantly increased prevalence of this variant in affected individuals compared to controls is available.	clinvar gnomad_v2 gnomad_v4
PS5	Not met	No RNA studies confirming that this variant causes aberrant splicing are available. SpliceAI predicts a strong splice-altering effect (DS_AG=0.98), but PS5 requires experimental confirmation of splicing disruption.	spliceai
PM1	Not met	This intronic variant (c.1555-13C>A) does not fall within a characterized functional domain residue or established mutational hotspot. No domain-level or residue-specific hotspot evidence supports PM1.
PM2	Met	This variant is extremely rare in population databases. It is completely absent from gnomAD v2.1 (0/250,694 alleles) and present at an allele frequency of 0.00031% (5/1,612,324 alleles) in gnomAD v4.1, with no homozygotes. This is well below the PM2 threshold of 0.1% for dominant disorders under generic ACMG.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a missense change at a residue where a different pathogenic missense change has been reported. This is an intronic substitution and does not produce a missense change.
PM6	Not met	No de novo observation (without confirmation of paternity/maternity) is available for this variant.
PP1	Not met	No co-segregation data with disease in multiple affected family members is available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This is an intronic substitution, not a missense variant.
PP3	Met	Multiple lines of in silico evidence predict a deleterious splice-altering effect. SpliceAI predicts a strong cryptic acceptor gain (DS_AG=0.98) and moderate acceptor loss (DS_AL=0.31). Pangolin supports a splice-gaining effect (SG=0.79, SL=-0.72). The high delta scores from two independent splice prediction tools support a damaging effect on splicing.	spliceai
PP4	Not met	No patient phenotype or family history data is available to assess specificity for a DNMT3A-related disorder (e.g., Tatton-Brown-Rahman syndrome or DNMT3A overgrowth syndrome).
PP5	Not met	This variant is absent from ClinVar; no reputable source has reported it as pathogenic.	clinvar
BA1	Not met	The allele frequency in population databases is 0.00031% (gnomAD v4.1), far below the BA1 threshold of >1% (non-VCEP generic ACMG).	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency of 0.00031% is below the BS1 threshold of >0.3% for a dominant disorder under non-VCEP generic ACMG.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous or hemizygous observations in healthy adults are reported in gnomAD; zero homozygotes across all population databases.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect on splicing or protein function are available for this variant.
BS4	Not met	No non-segregation with disease data is available for this variant.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This is an intronic substitution, not a missense variant.
BP2	Not met	No evidence of this variant observed in trans with a pathogenic variant in a recessive disorder. DNMT3A-related disorders (TBRS, DOS) are autosomal dominant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a substitution variant.
BP4	Not met	Multiple in silico tools (SpliceAI: DS_AG=0.98, Pangolin: SG=0.79) predict a deleterious splice-altering effect, contradicting the requirement for BP4 (multiple lines of computational evidence suggesting no impact).	spliceai
BP5	Not met	No evidence that this variant is found in a case with an alternate molecular basis for disease.
BP6	Not met	This variant is absent from ClinVar; no reputable source has reported it as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is an intronic substitution, not a synonymous variant.

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