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).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.2 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.3 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.4
DNMT3A
Final classification
VUS
DNMT3A c.1555-13C>A · p.?
DNMT3A
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).
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.
Classification rationale
PM2PP3
VUS
DNMT3A c.1555-13C>A
PM2 + PP3
→
VUS
Gene diagram
· NM_022552.4 · variants mapped to exon structure
DNMT3A
NM_022552.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: 0/250694 alleles (AF=0%)gnomAD v4.1: 5/1
✓
PP3
supporting
Pathogenic
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: DS_AG=0.98 (cryptic acceptor gainhigh confidence)DS_AL=0.31 (acceptor loss
Assessed · not applied
Pathogenic
PVS1
c.1555-13C>A is an intronic variant located 13bp upstream of exon 14, outside the canonical splice consensus (±1,2).
PS1
No known pathogenic variant has been reported at this same nucleotide position (c.1555-13) to support PS1.
PS2
No de novo data (with confirmed maternity and paternity) is available for this variant.
PS3
No experimental functional studies (in vitro or in vivo) have been identified for this variant.
PS4
No case-control data demonstrating significantly increased prevalence of this variant in affected individuals compared to controls is available.
PM1
This intronic variant (c.1555-13C>A) does not fall within a characterized functional domain residue or established mutational hotspot.
PM6
No de novo observation (without confirmation of paternity/maternity) is available for this variant.
PP1
No co-segregation data with disease in multiple affected family members is available for this variant.
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).
PP5
This variant is absent from ClinVar; no reputable source has reported it as pathogenic.
Benign
BA1
The allele frequency in population databases is 0.00031% (gnomAD v4.1), far below the BA1 threshold of >1% (non-VCEP generic ACMG).
BS1
The allele frequency of 0.00031% is below the BS1 threshold of >0.3% for a dominant disorder under non-VCEP generic ACMG.
BS2
No homozygous or hemizygous observations in healthy adults are reported in gnomAD; zero homozygotes across all population databases.
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.
BS4
No non-segregation with disease data is available for this variant.
BP2
No evidence of this variant observed in trans with a pathogenic variant in a recessive disorder.
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).
BP5
No evidence that this variant is found in a case with an alternate molecular basis for disease.
BP6
This variant is absent from ClinVar; no reputable source has reported it as benign.
N/A · 5
PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00031%
· 5 / 1,612,324
0 hom · FAF 0.00012%
0 hom · FAF 0.00012%
European (non-Finnish) 5 / 1,178,620 |
0.00042% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / 250,694
0 hom
0 hom
Not observed in any ancestry group.
+ 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.98).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links