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DICER1
Final classification
Benign
BA1BS1BS2BP4BP7
DICER1
c.4014G>A
p.Ala1338=
synonymous · exon 21
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

DICER1 is a tumor suppressor whose loss of function drives DICER1-related tumor susceptibility, so this variant's high population frequency (0.423% in Finnish gnomAD v4.1) and silent, splice-neutral profile (SpliceAI max delta 0.004) indicate it does not impair DICER1 function. It is therefore not expected to confer the cancer risk associated with DICER1 loss-of-function mutations.

Transcript
NM_177438.3
HGVS · transcript:coding
NM_177438.3:c.4014G>A
GRCh38
chr14:95103382 C>T
GRCh37
chr14:95569719 C>T
Basis Benign: -15 points (BA1 stand-alone -8, BS1 -4, BS2 -1, BP4 -1, BP7 -1) falls in the Rule5 range (<=-7) mapping to Benign. ▾
Benign: -15 points (BA1 stand-alone -8, BS1 -4, BS2 -1, BP4 -1, BP7 -1) falls in the Rule5 range (<=-7) mapping to Benign.
Classification rationale
BA1BS1BS2BP4BP7 Benign
DICER1 c.4014G>A synonymous · exon 21

BA1 (stand-alone benign): Finnish gnomAD v4.1 allele frequency 0.423% (271/64,026) exceeds the 0.3% subpopulation threshold. BS1 (strong): same Finnish allele frequency 0.423% exceeds the 0.03% subpopulation threshold. BS2 (supporting): 6 homozygotes in gnomAD v4.1 meet the 2+ homozygosity observation threshold. BP4 (supporting): SpliceAI predicts no splice effect (max delta 0.004). BP7 (supporting): silent variant p.(Ala1338=) meets the VCEP BP7 rule. Benign: combined -15 points under the DICER1 VCEP v1.4 point framework falls in the Rule5 range (<=-7).

BA1 + BS1 + BS2 + BP4 + BP7 → Benign
Gene diagram · NM_177438.3 · variants mapped to exon structure
DICER1 NM_177438.3
Fetching transcript structure from UCSC…
Applied criteria · 5 applied · 12 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 · 5
Strength Supporting Moderate Strong Very strong
✓
BA1 stand-alone Benign
Met (stand-alone benign): Finnish gnomAD v4.1 allele frequency 0.423% (271/64,026) exceeds the 0.3% BA1 threshold with sufficient allele counts.
The DICER1 VCEP Version 1.4 BA1 rule requires frequency >0.003 in a gnomAD subpopulation, with >2,000 alleles tested and at least 5 observed alleles.gnomAD v4.1 reports the variant in the Finnish subpopulation at 271/64,026 alleles (AF 0.0042326555; 0.42327%), exceeding the VCEP BA1 threshold and sample-size requirements.
cspec ↗gnomad_v4 ↗
✓
BS1 strong Benign
Met (strong): Finnish gnomAD v4.1 allele frequency 0.423% (271/64,026) exceeds the 0.03% BS1 threshold.
The DICER1 VCEP Version 1.4 BS1 rule requires frequency >0.0003 in a gnomAD subpopulation, with >2,000 alleles tested and at least 5 observed alleles.gnomAD v4.1 reports 271/64,026 Finnish alleles (AF 0.0042326555; 0.42327%), which is above the VCEP BS1 threshold and meets the required subpopulation size and allele-count thresholds.
cspec ↗gnomad_v4 ↗
✓
BS2 supporting Benign
Met (supporting): gnomAD v4.1 reports 6 homozygotes, meeting the threshold of 2+ homozygosity observations without clinical information.
The DICER1 VCEP Version 1.4 BS2 Supporting rule allows 2 or more homozygosity observations in individuals lacking clinical information.gnomAD v4.1 reports 6 homozygotes for the variant; no clinical phenotype or parental-confirmation data are provided in the case evidence.
cspec ↗gnomad_v4 ↗
✓
BP4 supporting review Benign
Met (supporting): SpliceAI predicts no splice effect (max delta 0.004). Flagged for human review: MaxEntScan concordance is not yet confirmed.
SpliceAI Lookup for NM_177438.3:c.4014G>A: DS_AG=0.002, DS_AL=0.002, DS_DG=0.002, DS_DL=0.004, max_delta_score=0.004 - evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).' (source: spliceai in source_registry).DICER1 VCEP (ClinGen, CSpec v1.4) 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.' (source: cspec)No MaxEntScan score was found anywhere in prefetch.json or evidence.json for this case; only SpliceAI splice-prediction data was available.
spliceai ↗cspec ↗
✓
BP7 supporting review Benign
Met (supporting): silent variant p.(Ala1338=) qualifies under the VCEP BP7 rule, contingent on BP4.
Normalization data (case_summary.json) confirms the variant is synonymous: NP_803187.1:p.(Ala1338=) / NP_803187.1:p.(A1338=).DICER1 VCEP (ClinGen, CSpec v1.4) 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' (source: cspec)SpliceAI Lookup for NM_177438.3:c.4014G>A: max_delta_score=0.004, no significant splice impact predicted, supporting the BP4 precondition for BP7 (source: spliceai in source_registry).
spliceai ↗cspec ↗
Assessed · not applied · 5 not met · 7 not assessed
Pathogenic
PS2 Not assessed: no parental testing, maternity/paternity confirmation, or de novo observations were available for this variant.
PS3 Not assessed: no RNA splicing or in vitro microRNA-cleavage assay data on this variant were available.
PS4 Not met: Finnish gnomAD v4.1 allele frequency 0.423% (271/64,026) exceeds the VCEP BA1 threshold of 0.3%, excluding PS4.
PM2 Not met: gnomAD v4.1 overall allele frequency 0.126% (2,039 alleles, 6 homozygotes) far exceeds the PM2 threshold of <0.0005%.
PP1 Not assessed: no affected relatives, genotype results, or meiosis counts were available to assess segregation.
PP3 Not met: SpliceAI max delta 0.004 is far below any splice-disruption threshold; REVEL does not apply to this synonymous variant.
PP4 Not assessed: no tumor-testing result demonstrating a somatic DICER1 hotspot second hit was supplied.
PP5 Not met: ClinVar variation 221087 has no expert-panel assertion, only ordinary clinical-laboratory submissions.
Benign
BS3 Not assessed: no RNA or in vitro cleavage assay data on this variant were available; in silico predictions do not qualify for BS3.
BS4 Not assessed: no pedigree or genotype-negative relatives were available to assess lack of segregation.
BP2 Not assessed: no second pathogenic DICER1 variant or cis/trans phase observation was available.
BP6 Not met: ClinVar Benign/Likely benign assertions are from ordinary laboratories with no expert-panel assertion.
N/A · 11 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · BP1 · BP3 · BP5
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= 0.00126318; MAF= 0.12632%, 2039/1614180 alleles, homozygotes = 6) and has highest observed frequency in the European (Finnish) population (AF= 0.00423266; MAF= 0.42327%, 271/64026 alleles, homozygotes = 1); grpmax FAF= 0.00135491.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00114029; MAF= 0.11403%, 322/282384 alleles, homozygotes = 2) and has highest observed frequency in the European (Finnish) population (AF= 0.00382105; MAF= 0.38210%, 96/25124 alleles, homozygotes = 1); grpmax FAF= 0.00263963.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0009233108842059526, 17/18412 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.13% · 2039 / 1,614,180
6 hom · FAF 0.14%
European (Finnish)
271 / 64,026
0.42%
1 hom
European (non-Finnish)
1666 / 1,180,028
0.14%
5 hom
Remaining individuals
59 / 62,506
0.094%
African/African American
26 / 75,044
0.035%
Middle Eastern
2 / 6,062
0.033%
Admixed American
14 / 60,028
0.023%
East Asian
1 / 44,886
0.0022%
+ 3 not observed (Amish, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.11% · 322 / 282,384
2 hom · FAF 0.26%
European (Finnish)
96 / 25,124
0.38%
1 hom
European (non-Finnish)
198 / 128,976
0.15%
1 hom
Remaining individuals
6 / 7,208
0.083%
African/African American
10 / 24,704
0.04%
Admixed American
11 / 35,436
0.031%
South Asian
1 / 30,614
0.0033%
+ 2 not observed (Ashkenazi Jewish, East Asian)
gnomAD Canada 🇨🇦
0.092% · 17 / 18,412
0 hom · FAF 0.092%
indel · split
European (non-Finnish)
17 / 11,732
0.14%
+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Benign (6 clinical laboratories) and as Likely benign (5 clinical laboratories). (ClinVarID = 221087)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.371.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58617078, n = 4 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 5 PMIDs 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
28524158 ↗ Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma. CLINVAR
24761742 ↗ DICER1-Related Tumor Predisposition. CLINVAR
25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR