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DICER1
Final classification
Likely Benign
BP4BP7
DICER1
c.735-23A>G
p.?
unknown · exon 6i
Gene context NCBI Gene ↗ OncoKB ↗

DICER1 encodes an enzyme that processes RNA into small silencing RNAs and microRNAs, which regulate gene expression after transcription. Germline mutations in DICER1 cause DICER1-related disorders, a familial tumor susceptibility syndrome that increases the risk of pleuropulmonary blastoma, cystic nephroma, rhabdomyosarcoma, multinodular goiter, and ovarian Sertoli-Leydig cell tumors. DICER1 acts as a tumor suppressor, and loss or reduced activity of the protein is linked to cancer development and poorer outcomes in several cancer types, including lung, breast, and ovarian cancers.

This variant

This deep intronic variant is predicted to have no effect on DICER1 splicing or protein production, so it is unlikely to impair the enzyme's tumor-suppressor function. Because loss of DICER1 function drives the familial tumor susceptibility seen in DICER1-related disorders, a variant with no predicted functional impact and no pathogenic criteria met is not expected to increase cancer risk. This supports the Likely Benign classification.

Transcript
NM_177438.3
HGVS · transcript:coding
NM_177438.3:c.735-23A>G
GRCh38
chr14:95126771 T>C
GRCh37
chr14:95593108 T>C
Basis Likely Benign: Tavtigian score -2 from BP4 (Supporting) and BP7 (Supporting), with no pathogenic criteria met under the DICER1 VCEP v1.4 framework. ▾
Likely Benign: Tavtigian score -2 from BP4 (Supporting) and BP7 (Supporting), with no pathogenic criteria met under the DICER1 VCEP v1.4 framework.
Classification rationale
BP4BP7 Likely Benign
DICER1 c.735-23A>G unknown · exon 6i

BP4 (Supporting): SpliceAI predicts no splicing effect for this intronic variant (max delta 0.001). BP7 (Supporting): intronic position -23 is beyond -21 from the acceptor site, and BP4 is met as required. Synthesis: a total Tavtigian score of -2 from the two supporting benign criteria classifies this variant as Likely Benign under the DICER1 VCEP v1.4 framework.

BP4 + BP7 → Likely Benign
Gene diagram · NM_177438.3 · variants mapped to exon structure
DICER1 NM_177438.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 13 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
✓
BP4 supporting Benign
Met (Supporting): SpliceAI predicts no splicing effect (max delta 0.001), satisfying the BP4 concordance rule for intronic variants.
SpliceAI Lookup result for NM_177438.3:c.735-23A>G: DS_AG=0.001, DS_AL=0.0, DS_DG=0.0, DS_DL=0.0, max delta score=0.001.DICER1 VCEP cspec BP4 rule: 'For missense variants, REVEL score < 0.500 and agreement in splicing predictors that no splicing effects are predicted. For synonymous/intronic/non-coding variants concordance of MaxEntScan and SpliceAI.'DICER1 VCEP cspec PP3/BP4 instructionsToUse: SpliceAI scores alone govern for variants outside the MES-validated acceptor range of intron -20 through exon+3; c.735-23 lies at position -23, outside this range.
cspec ↗spliceai ↗
✓
BP7 supporting Benign
Met (Supporting): intronic position -23 lies beyond -21 from the acceptor site, with no splicing impact predicted.
DICER1 VCEP cspec BP7 rule: 'Silent variant OR Intronic variant at or beyond +7 to -21 positions OR Other intronic or non-coding variant if the variant is the reference nucleotide in >=1 primate and/or >=4 mammalian species. Caveat: Variant must meet BP4 to apply BP7.'Variant position c.735-23A>G is at intron position -23, beyond the -21 threshold specified in the BP7 rule.BP4 determination (this group): SpliceAI max delta score 0.001, no splicing effect predicted, satisfying the BP4 prerequisite for BP7.
cspec ↗spliceai ↗
Assessed · not applied · 5 not met · 8 not assessed
Pathogenic
PS2 Not assessed: no de novo observation, parental genotypes, or confirmation data for this variant were available.
PS3 Not assessed: no RNA splicing or microRNA cleavage assay data for this variant were available.
PS4 Not assessed: no case series, unrelated-proband phenotype observations, or case-control counts were available.
PM2 Not met: gnomAD v4.1 frequency 1.38e-05 (21/1,521,894 alleles, 19 in European non-Finnish) exceeds the <0.000005 PM2 threshold.
PP1 Not assessed: no affected relatives, family structure, or meiosis-count data were available.
PP3 Not met: SpliceAI predicts no splicing effect (max delta 0.001), and the intronic variant falls outside the missense REVEL/BayesDel sub-path.
PP4 Not assessed: no tumor-testing or proband phenotype results for this variant were available.
Benign
BA1 Not met: highest gnomAD v4.1 subpopulation frequency 1.74e-05 (1/57,450) is far below the >0.003 BA1 threshold.
BS1 Not met: highest gnomAD v4.1 subpopulation frequency 1.74e-05 (1/57,450) is below the >0.0003 BS1 threshold.
BS2 Not met: gnomAD v4.1 reports zero homozygotes, and no healthy-individual or parental-testing observations were available.
BS3 Not assessed: no RNA or cleavage assay data demonstrating absence of splicing impact were available.
BS4 Not assessed: no genotype or phenotype data for first- to third-degree relatives were available.
BP2 Not assessed: no phase, parental, or second-variant data existed to evaluate the in trans/in cis threshold.
N/A · 13 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP3 · BP5 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.37986e-05; MAF= 0.00138%, 21/1521894 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.74064e-05; MAF= 0.00174%, 1/57450 alleles, homozygotes = 0); grpmax FAF= 1.096e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.20237e-05; MAF= 0.00120%, 3/249508 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.20732e-05; MAF= 0.00621%, 1/16110 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0014% · 21 / 1,521,894
0 hom · FAF 0.0011%
Admixed American
1 / 57,450
0.0017%
European (non-Finnish)
19 / 1,108,536
0.0017%
African/African American
1 / 67,676
0.0015%
+ 7 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0012% · 3 / 249,508
0 hom
African/African American
1 / 16,110
0.0062%
Admixed American
1 / 34,370
0.0029%
European (non-Finnish)
1 / 113,002
0.00088%
+ 5 not observed (Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 1802873)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
SpliceAI ↗
Functional No data
No calibrated functional assay or RNA evidence was identified for this variant.
OncoKB ↗
COSMIC screenshot
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.
COSMIC ↗
Sources & reference links
8Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Triaged references · 1 PMID not cited in assessment
25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR