NM_022552.4:c.2322+3A>G

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

GRCh37: chr2:25463168 T>C · GRCh38: chr2:25240299 T>C

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

6.815281099366798e-06 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_022552.4:c.2322+3A>G in DNMT3A is an intronic variant at the +3 position of intron 19, outside the canonical ±1,2 splice consensus.

This variant is present at extremely low frequency in gnomAD v4.1 (AF = 6.82×10⁻⁶, grpmax FAF = 2.47×10⁻⁶, no homozygotes), meeting PM2 at supporting strength.

SpliceAI predicts a splice-altering effect with a max delta score of 0.64, meeting PP3 at supporting strength.

This variant is absent from ClinVar and has not been reported in the medical literature; no experimental functional studies or segregation data are available.

Based on the generic ACMG/AMP 2015 framework, the total evidence (PM2_supporting + PP3_supporting) is insufficient to classify this variant as likely pathogenic or pathogenic. The variant is classified as a Variant of Uncertain Significance (VUS).

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	NM_022552.4:c.2322+3A>G is an intronic variant at the +3 position of intron 19, which is outside the canonical ±1,2 splice donor/acceptor consensus. The generic ClinGen SVI PVS1 framework (PMC6185798) applies only to nonsense, frameshift, canonical ±1,2 splice, initiation codon, and exon-level deletion variants. The PVS1 variant assessment confirmed this variant does not fall into any default null-variant bucket.	pvs1_generic_framework pvs1_variant_assessment spliceai
PS1	N/A	Intronic variant with no amino acid change; PS1 requires a different nucleotide change at the same amino acid position as an established pathogenic missense variant.
PS2	Not met	No de novo data are available for this variant. No published trio studies or clinical reports confirming de novo occurrence were identified.
PS3	Not met	No functional studies have been performed on this specific variant or a systematically characterized range that includes the c.2322+3 position. The COSMIC somatic occurrence (COSV53040203, n=1) does not constitute experimental functional evidence for germline variant interpretation.
PS4	Not met	No case-control data or statistical enrichment data are available for this variant. The variant is absent from ClinVar and no published patient cohorts reporting this variant were identified.
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion in the generic ACMG framework. No applicable evidence rule exists for this criterion code under generic_acmg mode.
PM1	Not met	This intronic variant at position c.2322+3 of intron 19 does not lie within a characterized protein functional domain (PWWP, ADD, or methyltransferase domains). The cancerhotspots.org database does not list this position as a mutational hotspot. While the SpliceAI prediction (delta 0.64) suggests a potential splicing effect, the variant does not localize to a well-established critical functional domain with limited benign variation.	spliceai
PM2	Met	This variant is present at extremely low frequency in population databases. In gnomAD v4.1, the allele frequency is 6.82×10⁻⁶ (11/1,614,020 alleles, no homozygotes) with a grpmax filtering allele frequency of 2.47×10⁻⁶, well below the 0.1% PM2 threshold. The highest subpopulation frequency is in the Finnish population at 3.12×10⁻⁵ (0.00312%).	gnomad_v2 gnomad_v4
PM5	N/A	Intronic variant with no amino acid change; PM5 requires a different pathogenic missense variant at the same amino acid residue. No protein-level comparator exists.	pm5_candidates
PM6	Not met	No de novo data are available for this variant. No published reports or clinical data confirming de novo occurrence in a trio were identified.
PP1	Not met	No segregation data are available for this variant. No family studies demonstrating cosegregation with disease have been reported.
PP2	N/A	Intronic variant; PP2 applies only to missense variants in genes with a low rate of benign missense variation.
PP3	Met	SpliceAI predicts a splice-altering effect for this variant with a maximum delta score of 0.64, which exceeds the 0.5 threshold considered predictive of splicing impact. REVEL and BayesDel scores are not available as this is an intronic variant outside coding sequence.	spliceai
PP4	Not met	No specific phenotype or clinical data for the proband are available for review. PP4 requires that the patient's phenotype or family history is highly specific for the disease associated with the gene.
PP5	Not met	This variant is absent from ClinVar. No reputable source (3-star expert panel or equivalent) has classified this variant as pathogenic.	clinvar
BA1	Not met	The variant allele frequency in gnomAD v4.1 (6.82×10⁻⁶) is far below the 1% BA1 threshold. The highest subpopulation frequency (Finnish, 3.12×10⁻⁵) also falls well below 1%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant allele frequency in gnomAD v4.1 (6.82×10⁻⁶) is far below the 0.3% BS1 threshold. The highest subpopulation frequency (Finnish, 3.12×10⁻⁵) also falls well below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No evidence is available for homozygous occurrence in healthy individuals or observation in trans with a pathogenic variant in a fully penetrant dominant disorder.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating a benign effect on protein function or splicing have been performed for this variant.
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease are available.
BP1	N/A	Intronic variant; BP1 applies only to missense variants in genes where a truncating mechanism is the primary cause of disease.
BP2	Not met	No data are available for observation of this variant in trans with a pathogenic variant in a fully penetrant dominant disorder.
BP4	Not met	SpliceAI predicts a splice-altering effect (max delta = 0.64), which contradicts BP4. Multiple lines of in silico evidence predicting no impact are required for BP4; instead, the available computational evidence predicts a potential effect on splicing.	spliceai
BP5	Not met	No data are available demonstrating that this variant is observed in a case with an established alternate molecular basis for disease.
BP6	Not met	This variant is absent from ClinVar. No reputable source has classified this variant as benign or likely benign.	clinvar
BP7	Not met	SpliceAI predicts a potential splice-altering effect (max delta = 0.64). BP7 requires synonymous or intronic variants where splicing algorithms predict no impact on the splice consensus sequence. The elevated SpliceAI score precludes application of BP7.	spliceai
BP3	N/A	Intronic variant; BP3 applies to in-frame deletions/insertions in repetitive regions.
PM3	N/A	No recessive inheritance data available; DNMT3A-associated disorders (Tatton-Brown-Rahman syndrome) follow autosomal dominant inheritance.
PM4	N/A	Intronic variant; PM4 applies to protein-length changing variants (in-frame deletions/insertions, stop-loss).

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