About DNMT3A
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
DNMT3A c.2322+3A>G, p.?
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
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%).
PP3Supporting
PP3 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
11 / 1,614,020 alleles
gnomAD v4.1: 11 / 1,614,020 alleles. Recorded AF 6.81528e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97798e-06; MAF= 0.00040%, 1/251384 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89201e-05; MAF= 0.00289%, 1/34578 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.640 maximum delta
Recorded SpliceAI maximum delta score: 0.640. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV53040203, n = 1 times).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 19 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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).
No criteria match.
Met · 2
PM2 SupportingThis 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%). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF = 6.82×10⁻⁶ (11/1
- 614
- 020)
- grpmax FAF = 2.47×10⁻⁶
- gnomAD v2.1: AF = 3.98×10⁻⁶ (1/251
- 384)
- Highest subpopulation AF (Finnish) = 3.12×10⁻⁵
- still well below 0.1%
- No homozygotes observed in any population database
Sources
PP3 SupportingSpliceAI 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.64 (above 0.5 high-impact threshold)
- Variant is at intron 19 +3 position
- within the splice donor region
Still missing
- SpliceAI prediction not confirmed by RNA studies or minigene assay
- REVEL/BayesDel not applicable for intronic variants
Sources
Not met · 19 · evaluated, threshold not reached
PVS1 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. Details ▾Hide ▴
Evidence considered
- Variant is at c.2322+3 (intronic +3 position)
- outside canonical ±1
- 2 splice consensus
- Generic PVS1 framework does not apply to non-canonical splice region variants
- SpliceAI max delta score = 0.64 indicates potential splicing impact but does not qualify this variant for the PVS1 null-variant framework
Still missing
- No RNA studies available to confirm splicing outcome
- No CSPEC/VCEP framework for DNMT3A to provide gene-specific PVS1 guidance
Sources
PS2 No de novo data are available for this variant. No published trio studies or clinical reports confirming de novo occurrence were identified. Details ▾Hide ▴
Evidence considered
- No de novo reports found in ClinVar
- literature
- or case data
Still missing
- Parental testing not available to assess de novo status
PS3 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. Details ▾Hide ▴
Evidence considered
- No variant-specific functional data available in the literature
- COSMIC entry (1 sample) does not provide functional characterization
Still missing
- RNA studies (e.g.
- minigene splicing assay
- patient RNA) needed to assess functional splicing impact
- No systematic mutagenesis or saturation screening data covering this splice region
PS4 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. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- No published case-control or cohort studies identified
Still missing
- No affected vs. control population data available
PM1 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. Details ▾Hide ▴
Evidence considered
- Variant is intronic
- not located in a protein functional domain
- Not listed as a significant residue at cancerhotspots.org
- No established mutational hotspot at this splice junction
Still missing
- Domain-level characterization of DNMT3A splice regions lacking
Sources
PM6 No de novo data are available for this variant. No published reports or clinical data confirming de novo occurrence in a trio were identified. Details ▾Hide ▴
Evidence considered
- No de novo reports found in any data source
Still missing
- Parental testing status unknown
PP1 No segregation data are available for this variant. No family studies demonstrating cosegregation with disease have been reported. Details ▾Hide ▴
Evidence considered
- No family segregation data available
Still missing
- Family history and segregation analysis not available
PP4 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. Details ▾Hide ▴
Evidence considered
- No proband phenotype data provided in case materials
Still missing
- Proband clinical phenotype and family history not available
PP5 This variant is absent from ClinVar. No reputable source (3-star expert panel or equivalent) has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- Variant not found in ClinVar
- No expert panel or reputable source classification available
Sources
BA1 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%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF = 6.82×10⁻⁶
- grpmax FAF = 2.47×10⁻⁶
- All population and subpopulation frequencies are well below 1%
Sources
BS1 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%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF = 6.82×10⁻⁶
- All population and subpopulation frequencies are well below 0.3%
Sources
BS2 No evidence is available for homozygous occurrence in healthy individuals or observation in trans with a pathogenic variant in a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- No homozygotes observed in gnomAD v2.1 or v4.1
- No cis/trans phase data available
Still missing
- No data on healthy homozygous carriers or trans observations
Sources
BS3 No functional studies demonstrating a benign effect on protein function or splicing have been performed for this variant. Details ▾Hide ▴
Evidence considered
- No functional data available showing normal splicing or protein function
Still missing
- No RNA studies or functional assays demonstrating normal splicing for this variant
BS4 No segregation data demonstrating lack of cosegregation with disease are available. Details ▾Hide ▴
Evidence considered
- No family segregation data available to assess non-segregation
Still missing
- Segregation analysis not available
BP2 No data are available for observation of this variant in trans with a pathogenic variant in a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- No evidence of co-occurrence in trans with a pathogenic variant
Still missing
- Phase information not available
BP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.64
- predicting potential splicing impact
- No in silico tools predict a benign or neutral effect
Sources
BP5 No data are available demonstrating that this variant is observed in a case with an established alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis data available
Still missing
- No data on alternate molecular diagnoses in carriers
BP6 This variant is absent from ClinVar. No reputable source has classified this variant as benign or likely benign. Details ▾Hide ▴
BP7 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.64 (above 0.5 threshold)
- predicting splicing alteration
- Variant is at the +3 intronic position within the splice donor region
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AIntronic variant with no amino acid change; PS1 requires a different nucleotide change at the same amino acid position as an established pathogenic missense variant. Details ▾Hide ▴
Evidence considered
- Variant is intronic (c.2322+3A>G)
- no amino acid change exists for comparison
PM3 N/ANo recessive inheritance data available; DNMT3A-associated disorders (Tatton-Brown-Rahman syndrome) follow autosomal dominant inheritance. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AIntronic variant; PM4 applies to protein-length changing variants (in-frame deletions/insertions, stop-loss). Details ▾Hide ▴
No further detail was recorded.
PM5 N/AIntronic variant with no amino acid change; PM5 requires a different pathogenic missense variant at the same amino acid residue. No protein-level comparator exists. Details ▾Hide ▴
Evidence considered
- Variant is intronic
- no amino acid residue is altered for PM5 comparison
Sources
pm5_candidates
PP2 N/AIntronic variant; PP2 applies only to missense variants in genes with a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
- Variant is intronic
- not a missense variant
BP1 N/AIntronic variant; BP1 applies only to missense variants in genes where a truncating mechanism is the primary cause of disease. Details ▾Hide ▴
Evidence considered
- Variant is intronic
- not a missense variant
BP3 N/AIntronic variant; BP3 applies to in-frame deletions/insertions in repetitive regions. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 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. Details ▾Hide ▴
Evidence considered
- Not a standard ACMG/AMP 2015 criterion
- no applicable framework rule
Identifiers
- Gene
- DNMT3A
- Transcript
- NM_022552.4
- Coding (HGVS c.)
- NM_022552.4:c.2322+3A>G
- Protein (HGVS p.)
- NP_072046.2:p.?
- GRCh38
- chr2:25240299 T>C
- GRCh37
- chr2:25463168 T>C
- COSMIC
- COSV53040203
Gene diagram
Every interpreted variant in DNMT3A, mapped onto the exon structure of NM_022552.4. Select a row to find it on the plot.
DNMT3ANM_022552.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in DNMT3A
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
11 / 1,614,020 alleles
AF 6.82e-06 · 0 homozygotes · FAF 2.47e-06
gnomAD v2.1
1 / 251,384 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.8e-06 · 11 / 1,614,020 alleles · 0 hom · FAF 2.5e-06
| European (Finnish)2 / 64,024 | 3.1e-05 |
| Admixed American1 / 59,998 | 1.7e-05 |
| Remaining individuals1 / 62,484 | 1.6e-05 |
| European (non-Finnish)7 / 1,179,988 | 5.9e-06 |
0 alternate alleles recorded in 6 other groups: Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 251,384 alleles · 0 hom
| Admixed American1 / 34,578 | 2.9e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.81528e-06; MAF= 0.00068%, 11/1614020 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 3.12383e-05; MAF= 0.00312%, 2/64024 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97798e-06; MAF= 0.00040%, 1/251384 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89201e-05; MAF= 0.00289%, 1/34578 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingSpliceAI 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.64 (above 0.5 high-impact threshold)
- Variant is at intron 19 +3 position
- within the splice donor region
Still missing
- SpliceAI prediction not confirmed by RNA studies or minigene assay
- REVEL/BayesDel not applicable for intronic variants
Sources
BP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.64
- predicting potential splicing impact
- No in silico tools predict a benign or neutral effect
Sources
BP7 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.64 (above 0.5 threshold)
- predicting splicing alteration
- Variant is at the +3 intronic position within the splice donor region
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.64).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
11 / 1,614,020 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.640
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_022552.4%3Ac.2322%2B3A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-25463168-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-25240299-T-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-25240299-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_022552.4%3Ac.2322…
- OncoKB ↗www.oncokb.org/gene/DNMT3A/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=122001809
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.81528e-06; MAF= 0.00068%, 11/1614020 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 3.12383e-05; MAF= 0.00312%, 2/64024 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97798e-06; MAF= 0.00040%, 1/251384 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89201e-05; MAF= 0.00289%, 1/34578 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.64).
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV53040203, n = 1 times).