About DNMT3A
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
DNMT3A c.1555-13C>A, 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 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.
PP3Supporting
PP3 · supporting
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.
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
5 / 1,612,324 alleles
gnomAD v4.1: 5 / 1,612,324 alleles. Recorded AF 3.10111e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/250694 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16220 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.980 maximum delta
Recorded SpliceAI maximum delta score: 0.980. 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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
27 criteria with recorded statuses: 2 met · 20 not met · 0 not assessed · 5 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.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.
No criteria match.
Met · 2
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0/250
- 694 alleles (AF=0%)
- gnomAD v4.1: 5/1
- 612
- 324 alleles (AF=0.00031%)
- No homozygotes in any population database
- grpmax FAF=1.24e-06
Sources
PP3 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- SpliceAI: DS_AG=0.98 (cryptic acceptor gain
- high confidence)
- DS_AL=0.31 (acceptor loss
- moderate)
- SpliceAI: DP_AG=-2 (novel acceptor 2bp from variant)
- DP_AL=-13 (native acceptor at variant position)
- Pangolin: SG=0.79 (splice gain)
- SL=-0.72 (splice loss)
- No REVEL/BayesDel scores available (intronic variant)
Sources
Not met · 20 · evaluated, threshold not reached
PVS1 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. Details ▾Hide ▴
Evidence considered
- Variant is intronic at c.1555-13 (non-canonical splice position)
- SpliceAI DS_AG=0.98 (predicted cryptic acceptor gain) and DS_AL=0.31 (predicted acceptor loss)
- No RNA studies confirming aberrant splicing available
- PVS1 variant assessment classifies this as bucket 'other' — does not qualify for generic PVS1
Still missing
- RNA studies (e.g.
- RT-PCR from patient sample) would be needed to confirm aberrant splicing and potentially elevate to PVS1
Sources
PS1 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. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no comparator pathogenic variant at the same nucleotide position
Sources
PS2 No de novo data (with confirmed maternity and paternity) is available for this variant. Details ▾Hide ▴
Still missing
- De novo testing with parental confirmation would be required
PS3 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. Details ▾Hide ▴
Evidence considered
- SpliceAI DS_AG=0.98 predicts cryptic acceptor gain
- but this is computational prediction
- not experimental functional evidence
- No publications with functional data for this variant were identified
Still missing
- RNA studies or minigene splicing assays would be needed to provide functional evidence
Sources
PS4 No case-control data demonstrating significantly increased prevalence of this variant in affected individuals compared to controls is available. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar (no case reports)
- Present in only 5/1
- 612
- 324 alleles in gnomAD v4.1 (no enriched affected cohort)
Still missing
- Case-control studies would be needed to assess enrichment
Sources
PM1 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. Details ▾Hide ▴
Evidence considered
- Intronic variant
- not within a protein functional domain
- No cancerhotspots.org residue-level hotspot data
PM6 No de novo observation (without confirmation of paternity/maternity) is available for this variant. Details ▾Hide ▴
Still missing
- De novo observation data would be required
PP1 No co-segregation data with disease in multiple affected family members is available for this variant. Details ▾Hide ▴
Still missing
- Family segregation data would be required
PP4 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). Details ▾Hide ▴
Still missing
- Patient phenotype and family history data would be needed
PP5 This variant is absent from ClinVar; no reputable source has reported it as pathogenic. Details ▾Hide ▴
BA1 The allele frequency in population databases is 0.00031% (gnomAD v4.1), far below the BA1 threshold of >1% (non-VCEP generic ACMG). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF=0.00031% (5/1
- 612
- 324 alleles)
- gnomAD v2.1: AF=0% (0/250
- 694 alleles)
Sources
BS1 The allele frequency of 0.00031% is below the BS1 threshold of >0.3% for a dominant disorder under non-VCEP generic ACMG. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF=0.00031% (<0.3% threshold)
- gnomAD v2.1: AF=0%
Sources
BS2 No homozygous or hemizygous observations in healthy adults are reported in gnomAD; zero homozygotes across all population databases. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0 homozygotes
- gnomAD v4.1: 0 homozygotes
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect on splicing or protein function are available for this variant. Details ▾Hide ▴
Still missing
- Functional studies (e.g.
- RNA analysis
- minigene assay) would be needed to demonstrate a benign effect
BS4 No non-segregation with disease data is available for this variant. Details ▾Hide ▴
Still missing
- Family segregation data would be required to demonstrate non-segregation
BP2 No evidence of this variant observed in trans with a pathogenic variant in a recessive disorder. DNMT3A-related disorders (TBRS, DOS) are autosomal dominant. Details ▾Hide ▴
Evidence considered
- DNMT3A-associated conditions are autosomal dominant
- BP2 is not applicable in trans context
BP4 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). Details ▾Hide ▴
Evidence considered
- SpliceAI: DS_AG=0.98 predicts strong cryptic acceptor gain
- Pangolin: SG=0.79 predicts splice gain
- Computational evidence supports a damaging effect
- not a benign one
Sources
BP5 No evidence that this variant is found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- Data on alternate molecular diagnoses in carriers would be required
BP6 This variant is absent from ClinVar; no reputable source has reported it as benign. Details ▾Hide ▴
PS5 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. Details ▾Hide ▴
Evidence considered
- SpliceAI DS_AG=0.98 predicts cryptic acceptor gain
- suggesting possible splicing disruption
- No RNA studies or minigene assays available to confirm the prediction
Still missing
- RNA studies (RT-PCR
- minigene splicing assay) from patient sample required
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PM5 N/APM5 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. Details ▾Hide ▴
No further detail was recorded.
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This is an intronic substitution, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This is an intronic substitution, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is an intronic substitution, not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- DNMT3A
- Transcript
- NM_022552.4
- Coding (HGVS c.)
- NM_022552.4:c.1555-13C>A
- Protein (HGVS p.)
- NP_072046.2:p.?
- GRCh38
- chr2:25244665 G>T
- GRCh37
- chr2:25467534 G>T
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
5 / 1,612,324 alleles
AF 3.1e-06 · 0 homozygotes · FAF 1.24e-06
gnomAD v2.1
0 / 250,694 alleles
AF 0 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 3.1e-06 · 5 / 1,612,324 alleles · 0 hom · FAF 1.2e-06
| European (non-Finnish)5 / 1,178,620 | 4.2e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 0 · 0 / 250,694 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.10111e-06; MAF= 0.00031%, 5/1612324 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.24225e-06; MAF= 0.00042%, 5/1178620 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/250694 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16220 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 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- SpliceAI: DS_AG=0.98 (cryptic acceptor gain
- high confidence)
- DS_AL=0.31 (acceptor loss
- moderate)
- SpliceAI: DP_AG=-2 (novel acceptor 2bp from variant)
- DP_AL=-13 (native acceptor at variant position)
- Pangolin: SG=0.79 (splice gain)
- SL=-0.72 (splice loss)
- No REVEL/BayesDel scores available (intronic variant)
Sources
BP4 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). Details ▾Hide ▴
Evidence considered
- SpliceAI: DS_AG=0.98 predicts strong cryptic acceptor gain
- Pangolin: SG=0.79 predicts splice gain
- Computational evidence supports a damaging effect
- not a benign one
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is an intronic substitution, not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.98).
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
5 / 1,612,324 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.980
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.1555-13C%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-25467534-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-25244665-G-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-25244665-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_022552.4%3Ac.1555…
- OncoKB ↗www.oncokb.org/gene/DNMT3A/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=DNMT3A+c.1555-13C%3EA
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= 3.10111e-06; MAF= 0.00031%, 5/1612324 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.24225e-06; MAF= 0.00042%, 5/1178620 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/250694 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16220 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 = 0.98).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).