Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
This variantScenario
BenignPathogenic
Benign.A benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
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About DICER1
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.
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01The reasoning
How it was classified
The recorded framework is ClinGen DICER1 VCEP v1.4. 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.
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 5
BA1Stand alone
BA1 · stand alone
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.
BS1Strong
BS1 · strong
Met (strong): Finnish gnomAD v4.1 allele frequency 0.423% (271/64,026) exceeds the 0.03% BS1 threshold.
BS2Supporting
BS2 · supporting
Met (supporting): gnomAD v4.1 reports 6 homozygotes, meeting the threshold of 2+ homozygosity observations without clinical information.
BP4Supporting
BP4 · supporting
Met (supporting): SpliceAI predicts no splice effect (max delta 0.004). Flagged for human review: MaxEntScan concordance is not yet confirmed.
BP7Supporting
BP7 · supporting
Met (supporting): silent variant p.(Ala1338=) qualifies under the VCEP BP7 rule, contingent on BP4.
Recorded classification: 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.
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
2,039 / 1,614,180 alleles
gnomAD v4.1: 2,039 / 1,614,180 alleles. Recorded AF 0.00126318. Recorded homozygote count 6.
gnomAD 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.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0009233108842059526, 17/18412 alleles, homozygotes = 0).
ACMG/AMP criteria under ClinGen DICER1 VCEP v1.4, with the data and sources behind each one.
28 criteria with recorded statuses: 5 met · 5 not met · 7 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Variant NM_177438.3:c.4014G>A is a synonymous substitution (NP_803187.1:p.(Ala1338=)) with no amino-acid change, no protein truncation, no frameshift, no canonical splice-site disruption, and no in-frame indel.
PVS1 does not apply because the variant is not a nonsense, frameshift, canonical splice-consensus, or other null-variant class recognized by the DICER1 VCEP PVS1 rule.
PM4 does not apply because the variant produces no protein length change (not an in-frame indel).
BP3 is explicitly Not Applicable for DICER1 per the VCEP CSPEC v1.4, and would not apply generically either given the variant is not an in-frame indel.
NM_177438.3:c.4014G>A is synonymous, NP_803187.1:p.(Ala1338=); it does not alter the encoded amino acid, so PS1 and PM5 (both defined in this cspec strictly for missense-to-missense comparisons) do not apply.
Residue 1338 lies outside the RNase IIIb domain (p.Y1682-p.S1846) and is not one of the seven metal ion-binding hotspot codons, so PM1's domain/hotspot tiers do not apply, independent of the synonymous status.
PP2 and BP1 are both explicitly flagged as Not Applicable in the DICER1 cspec itself, so neither criterion is assessable under the governing gene-specific framework regardless of variant type.
No literature source in this case's paper_extracts (PMID:25394175, PMID:25741868, PMID:28524158) mentions this variant, this residue, or a same-residue/same-codon comparator; none provide evidentiary support for any of the five criteria in this group.
DICER1 VCEP cspec v1.4 was used as the governing framework for both PS3 and BS3 (retrieved from case_summary.json / vcep_materials.json).
Neither criterion could be assessed because no RNA splicing assay or in vitro pre-miRNA cleavage assay evidence for this exact variant (NM_177438.3:c.4014G>A) was present in any bundled source (prefetch, evidence, literature_pass, paper_extracts, vcep_materials).
All three full-text literature sources tied to this case's ClinVar record were checked via paper_extracts.json and confirmed not to mention or functionally characterize this variant.
Variant NM_177438.3:c.4014G>A is synonymous (NP_803187.1:p.(Ala1338=)), so the REVEL-based missense path of PP3/BP4 does not apply; only the splicing in-silico path (SpliceAI, and MaxEntScan per VCEP text) is relevant for this group.
SpliceAI predicts no significant splice impact (max delta score = 0.004), which rules out PP3 and supports BP4/BP7 per the DICER1 VCEP CSpec v1.4.
MaxEntScan data was not present anywhere in this case's evidence bundle (prefetch.json/evidence.json), so the DICER1 VCEP's explicit requirement of MaxEntScan+SpliceAI concordance for BP4 could not be fully verified from two independent tools; BP4 and the dependent BP7 are applied at Supporting strength based on the unambiguous SpliceAI null result, with needs_human_review flagged.
No paper_extracts.json entries address splicing evidence for this variant; the three extracted papers (PMID:25394175, PMID:25741868, PMID:28524158) do not mention c.4014G>A or DICER1 splicing effects and were not used for this group's criteria.
No criteria match.
Met · 5
BA1Stand aloneMet (stand-alone benign): Finnish gnomAD v4.1 allele frequency 0.423% (271/64,026) exceeds the 0.3% BA1 threshold with sufficient allele counts.
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Reasoning
The DICER1 VCEP specifies BA1 when the allele frequency is >0.003 (0.3%) in a gnomAD subpopulation, with >2,000 alleles tested and at least 5 alleles present. In gnomAD v4.1, the Finnish subpopulation has 271 alternate alleles among 64,026 tested alleles (AF 0.00423266, 0.42327%), satisfying all three requirements.
Rule
Frequency >0.003 (0.3%) in gnomAD subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.
Evidence considered
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.
BS1StrongMet (strong): Finnish gnomAD v4.1 allele frequency 0.423% (271/64,026) exceeds the 0.03% BS1 threshold.
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Reasoning
The DICER1 VCEP specifies BS1 when the allele frequency is >0.0003 (0.03%) in a gnomAD subpopulation, with >2,000 alleles tested and at least 5 alleles present. In gnomAD v4.1, the Finnish subpopulation has 271 alternate alleles among 64,026 tested alleles (AF 0.00423266, 0.42327%), satisfying the VCEP BS1 rule.
Rule
Frequency >0.0003 (0.03%) in gnomAD subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.
Evidence considered
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.
BS2SupportingMet (supporting): gnomAD v4.1 reports 6 homozygotes, meeting the threshold of 2+ homozygosity observations without clinical information.
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Reasoning
The DICER1 VCEP permits BS2 Supporting for 2 or more observations of homozygosity in individuals lacking clinical information. gnomAD v4.1 reports 6 homozygotes overall, meeting this observation threshold. The database does not establish that these individuals are clinically healthy, so the VCEP's supporting-level provision for individuals lacking clinical information is used rather than the stronger healthy-individual provision.
Rule
Supporting: 2+ observations of homozygosity in individuals lacking clinical information.
Evidence considered
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.
Still missing
Clinical status and parental confirmation are not available for the six gnomAD v4.1 homozygote observations.
BP4SupportingMet (supporting): SpliceAI predicts no splice effect (max delta 0.004). Flagged for human review: MaxEntScan concordance is not yet confirmed.
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Reasoning
The DICER1 VCEP (CSpec v1.4) BP4 rule for synonymous/intronic/non-coding variants requires concordance of MaxEntScan and SpliceAI predicting no splicing effect. SpliceAI predicts a negligible splice impact for this variant (DS_AG=0.002, DS_AL=0.002, DS_DG=0.002, DS_DL=0.004; max delta=0.004), which is an unambiguous null/no-effect result. MaxEntScan output was not present anywhere in this case's evidence bundle, so the two-tool concordance specified by the VCEP text could not be independently confirmed from a second predictor; BP4 is applied at Supporting strength based on the single available, strongly negative SpliceAI signal, flagged for human confirmation of MaxEntScan concordance.
Rule
DICER1 VCEP CSpec v1.4 BP4: for synonymous/intronic/non-coding variants, concordance of MaxEntScan and SpliceAI predicting no splicing effect.
Evidence considered
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.
Still missing
MaxEntScan splice score was not present in the evidence bundle (prefetch.json/evidence.json only contain SpliceAI); the DICER1 VCEP BP4 rule for synonymous variants specifies concordance of MaxEntScan AND SpliceAI, so full two-tool concordance could not be independently verified from the available evidence.
BP7SupportingMet (supporting): silent variant p.(Ala1338=) qualifies under the VCEP BP7 rule, contingent on BP4.
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Reasoning
NM_177438.3:c.4014G>A is a silent (synonymous) variant, NP_803187.1:p.(Ala1338=), which meets the DICER1 VCEP BP7 rule ('Silent variant'). The VCEP BP7 rule carries the explicit caveat that the variant must meet BP4 to apply BP7; BP4 (Supporting) was applied above based on a strongly negative SpliceAI signal (max delta score = 0.004), though full two-predictor (MaxEntScan+SpliceAI) concordance could not be independently confirmed since MaxEntScan data was not present in this case's evidence bundle. BP7 Supporting is therefore applied conditional on that same caveat, flagged for human review.
Rule
DICER1 VCEP CSpec v1.4 BP7: silent variant (or qualifying intronic/non-coding variant), applicable only if BP4 is also met.
Evidence considered
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).
Still missing
BP7 application is contingent on the BP4 caveat, which itself carries an unresolved gap: MaxEntScan splice score was not available to confirm two-tool concordance alongside SpliceAI.
PS4Not met: Finnish gnomAD v4.1 allele frequency 0.423% (271/64,026) exceeds the VCEP BA1 threshold of 0.3%, excluding PS4.
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Reasoning
PS4 is excluded under the DICER1 VCEP specification when BA1 or BS1 frequency criteria are met. This exact variant has a Finnish gnomAD v4.1 allele frequency of 0.00423266 (271/64,026), above the VCEP BA1 threshold of 0.003 in a subpopulation with more than 2,000 alleles and at least five alleles. No case-control enrichment or qualifying phenotype-point observations were supplied.
Rule
DICER1 VCEP v1.4 PS4: do not apply if BA1/BS1 is met; otherwise >=4, 2-3.5, or 1-1.5 qualifying phenotype points correspond to Strong, Moderate, or Supporting evidence.
Evidence considered
The DICER1 VCEP PS4 rule assigns phenotype-point strengths but states: do not apply PS4 if the variant meets BA1/BS1.
gnomAD v4.1 reports Finnish AF 0.00423266 (271/64,026 alleles; one homozygote) for NC_000014.9:g.95103382C>T, the genomic representation of NM_177438.3:c.4014G>A.
PM2Not met: gnomAD v4.1 overall allele frequency 0.126% (2,039 alleles, 6 homozygotes) far exceeds the PM2 threshold of <0.0005%.
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Reasoning
The DICER1 VCEP PM2 Supporting rule requires allele frequency <0.000005 across gnomAD, no more than one allele in any subpopulation, and at least 20x coverage. The variant is common enough in gnomAD v4.1 to fail these requirements: overall AF is 0.00126318 with 2,039 alternate alleles and 6 homozygotes, and the Finnish subpopulation AF is 0.00423266 with 271 alternate alleles. The gnomAD v2.1 and gnomAD-Canada observations also show the variant is present at frequencies well above the PM2 threshold.
Rule
Allele frequency <0.000005 across gnomAD with no more than one allele in any subpopulation and at least 20x coverage.
Evidence considered
The DICER1 VCEP Version 1.4 PM2 Supporting rule requires AF <0.000005 across gnomAD, no more than one allele in any subpopulation, and at least 20x coverage.
gnomAD v4.1 reports overall AF 0.00126318 (2,039/1,614,180 alleles; 6 homozygotes) and Finnish AF 0.0042326555 (271/64,026 alleles), directly excluding PM2.
gnomAD v2.1 reports overall AF 0.00114029 (322/282,384 alleles; 2 homozygotes) and Finnish AF 0.00382105 (96/25,124 alleles; 1 homozygote).
gnomAD-Canada reports AF 0.00092331 (17/18,412 alleles; 0 homozygotes).
PP3Not met: SpliceAI max delta 0.004 is far below any splice-disruption threshold; REVEL does not apply to this synonymous variant.
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Reasoning
NM_177438.3:c.4014G>A is a synonymous variant (NP_803187.1:p.(Ala1338=)); REVEL is not applicable since the variant is not missense. The DICER1 VCEP (CSpec v1.4) PP3 rule requires either REVEL >= 0.750 for missense variants or predicted splicing effects for splicing/synonymous variants. SpliceAI predicts no significant splice impact for this variant across all four delta-score metrics (DS_AG=0.002, DS_AL=0.002, DS_DG=0.002, DS_DL=0.004; max delta=0.004), far below any threshold consistent with splice disruption. There is no in-silico signal supporting a pathogenic splicing effect, so PP3 is not met.
Rule
DICER1 VCEP CSpec v1.4 PP3: missense REVEL>=0.750 OR splicing predictor agreement predicting splicing effects; for splicing-relevant variants, concordance of MaxEntScan and SpliceAI.
Evidence considered
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 - no significant splice impact predicted (source: spliceai in source_registry).
DICER1 VCEP (ClinGen, CSpec v1.4) PP3 rule: 'For missense variants, REVEL score >= 0.750 OR agreement in splicing predictors predict splicing effects. For splicing variants, concordance of MaxEntScan and SpliceAI.' (source: cspec)
Variant is synonymous (NP_803187.1:p.(Ala1338=)), so the missense REVEL threshold does not apply; REVEL score of 0.371 reported in evidence.json is not relevant to a synonymous change and was not used for PP3.
PP5Not met: ClinVar variation 221087 has no expert-panel assertion, only ordinary clinical-laboratory submissions.
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Reasoning
ClinVar variation 221087 exactly matches NM_177438.3:c.4014G>A, but its submissions are ordinary clinical-laboratory submissions and ClinVar reports no expert-panel assertion. Therefore no exact-variant expert-panel Pathogenic/Likely pathogenic classification is available.
Rule
Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.
Evidence considered
ClinVar identifies the exact variant as NM_177438.3(DICER1):c.4014G>A (p.Ala1338=), with an empty expert_panels field and single-submitter laboratory classifications rather than an expert-panel Pathogenic/Likely pathogenic assertion.
Still missing
An exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion.
BP6Not met: ClinVar Benign/Likely benign assertions are from ordinary laboratories with no expert-panel assertion.
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Reasoning
ClinVar variation 221087 exactly matches NM_177438.3:c.4014G>A, but its Benign/Likely benign assertions are from ordinary clinical laboratories and no expert-panel assertion is present. Aggregate and non-expert assertions cannot support BP6.
Rule
Apply BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign classification.
Evidence considered
ClinVar reports Benign and Likely benign laboratory submissions for the exact variant, with review status criteria provided by multiple submitters and no conflicts, but source data show no expert-panel classification.
Still missing
An exact-variant ClinVar expert-panel Benign or Likely benign assertion.
PS2Not assessed: no parental testing, maternity/paternity confirmation, or de novo observations were available for this variant.
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Reasoning
The DICER1 VCEP specification permits PS2 using de novo points, requiring documented de novo status with maternity and paternity confirmed and a phenotype-consistent affected proband. The case-evidence bundle contains no proband-level parental testing, maternity/paternity confirmation, family-history assessment, or other de novo observations for NM_177438.3:c.4014G>A; therefore no PS2 points can be assigned.
Rule
PS2 is applicable; apply strength from the DICER1 VCEP de novo-point thresholds: Supporting for >=0.5 and <1 point, Moderate for >=1 and <2 points, Strong for >=2 and <4 points, and Very Strong for >=4 points.
Evidence considered
The DICER1 VCEP Version 1.4 rule states that PS2 de novo points are tallied using the proband-point table and that PS2, rather than PM6, is used for de novo evidence.
The DICER1 VCEP PS2 rule requires de novo status with both maternity and paternity confirmed; no such case-specific testing or de novo observation is documented in the consolidated evidence bundle.
Still missing
Documented proband phenotype consistent with DICER1-related tumor predisposition
Parental genotypes demonstrating absence of the variant in both biological parents
Confirmation of maternity and paternity
Assessment that the proband has no relevant family history
Any additional independent de novo observations, if available
PS3Not assessed: no RNA splicing or in vitro microRNA-cleavage assay data on this variant were available.
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Reasoning
The DICER1 VCEP specification (cspec v1.4) defines PS3 for this gene as requiring either (a) an RNA assay demonstrating a splicing impact, or (b) an in vitro pre-miRNA cleavage assay showing failure/reduced capacity to produce 5p or 3p microRNAs, with appropriate positive and negative controls. No RNA splicing assay, minigene assay, or in vitro cleavage assay data for NM_177438.3:c.4014G>A (p.(Ala1338=)) was found anywhere in the case evidence bundle (prefetch, evidence, literature_pass, paper_extracts, or vcep_materials). The three full-text papers with extracted findings (PMID:25394175, PMID:25741868, PMID:28524158) were confirmed not to mention this variant at all; none report functional assay data on it. No functional evidence source is available to adjudicate PS3.
Evidence considered
case_summary.json / vcep_materials.json cspec DICER1 v1.4 PS3 rule requires RNA assay (splicing impact, strong/moderate strength) or in vitro cleavage assay (supporting strength) with positive/negative controls
paper_extracts.json confirms PMID:25394175, PMID:25741868, PMID:28524158 do not mention DICER1 c.4014G>A or NP_803187.1:p.(A1338=), and none report functional assay results applicable to this variant
No functional/RNA/cleavage assay entries present anywhere in prefetch.json, evidence.json, or literature_pass.json for this variant
Still missing
No RNA splicing assay or minigene assay data available for c.4014G>A
No in vitro pre-miRNA cleavage assay data available for c.4014G>A
None of the retrieved/full-text literature (PMID:25394175, PMID:25741868, PMID:28524158) mentions this variant or reports functional characterization of it
PP1Not assessed: no affected relatives, genotype results, or meiosis counts were available to assess segregation.
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Reasoning
The DICER1 VCEP permits PP1 for co-segregation of phenotype-positive relatives, with Supporting strength for 3-4 meioses, Moderate for 5-6 meioses, and Strong for at least 7 meioses across at least 2 families. The case-evidence bundle provides no affected relatives, genotype results, family structure, or meiosis count for this variant, so segregation cannot be assessed.
Rule
PP1 is applicable only when informative co-segregation is documented; DICER1 VCEP thresholds are Supporting for 3-4 meioses, Moderate for 5-6 meioses, and Strong for >=7 meioses across >=2 families.
Evidence considered
The DICER1 VCEP PP1 rule requires phenotype-positive individuals and assigns strength according to informative meioses: 3-4 Supporting, 5-6 Moderate, and at least 7 across at least 2 families Strong.
No family segregation observations, relative genotypes, phenotype-positive relatives, or meioses are reported in the consolidated case-evidence bundle.
Still missing
Pedigree or family structure identifying informative relatives
Phenotype status and phenotype specificity for each relative
Variant genotype results for relatives
Number of informative meioses and number of families
PP4Not assessed: no tumor-testing result demonstrating a somatic DICER1 hotspot second hit was supplied.
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Reasoning
No tumor-testing result was supplied demonstrating the required DICER1 somatic hotspot second hit with retention of the germline variant and no additional somatic DICER1 loss-of-function variant.
Rule
DICER1 VCEP v1.4 PP4 Supporting: qualifying somatic hotspot second hit, retention of the assessed germline variant, and no additional somatic DICER1 non-hotspot variants.
Evidence considered
The DICER1 VCEP PP4 specification requires a tumor from a DICER1-associated neoplasm to retain the germline variant and to have a reported RNase IIIb hotspot second hit (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, or p.E1813), without additional somatic DICER1 non-hotspot variants.
Still missing
Tumor sequencing of a DICER1-associated neoplasm, including germline-variant retention, a qualifying RNase IIIb hotspot second hit, and assessment for additional somatic DICER1 non-hotspot variants.
BS3Not assessed: no RNA or in vitro cleavage assay data on this variant were available; in silico predictions do not qualify for BS3.
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Reasoning
The DICER1 VCEP specification (cspec v1.4) defines BS3 for this synonymous variant class as requiring an RNA assay showing no splicing impact (Strong, observed more than once) or an in vitro cleavage assay demonstrating normal production of both 5p and 3p microRNAs with appropriate controls (Supporting). No RNA splicing assay, minigene assay, or in vitro cleavage assay data for NM_177438.3:c.4014G>A (p.(Ala1338=)) was found anywhere in the case evidence bundle. In silico splicing predictions (e.g., SpliceAI) present in the bundle are relevant to BP4/BP7, not BS3, since BS3 under this VCEP specification requires actual functional/RNA assay data, not predictive tools. No functional evidence source is available to adjudicate BS3.
Evidence considered
case_summary.json / vcep_materials.json cspec DICER1 v1.4 BS3 rule requires RNA assay (no splicing impact, observed more than once, Strong) or in vitro cleavage assay showing normal 5p/3p microRNA production with controls (Supporting)
paper_extracts.json confirms PMID:25394175, PMID:25741868, PMID:28524158 do not mention DICER1 c.4014G>A or NP_803187.1:p.(A1338=), and none report functional assay results applicable to this variant
No functional/RNA/cleavage assay entries present anywhere in prefetch.json, evidence.json, or literature_pass.json for this variant; SpliceAI predictions present in the bundle pertain to in silico prediction criteria (BP4/BP7), not the assay-based BS3 rule
Still missing
No RNA splicing assay (e.g., RT-PCR/minigene) data demonstrating absence of splicing impact for c.4014G>A
No in vitro pre-miRNA cleavage assay data showing normal 5p/3p microRNA production for c.4014G>A
None of the retrieved/full-text literature (PMID:25394175, PMID:25741868, PMID:28524158) mentions this variant or reports functional characterization of it
BS4Not assessed: no pedigree or genotype-negative relatives were available to assess lack of segregation.
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Reasoning
The DICER1 VCEP permits BS4 at Strong strength when phenotype-positive first-, second-, or third-degree relatives of the proband are genotype-negative. The case-evidence bundle contains no relevant pedigree, phenotype-positive relatives, or genotype-negative relatives, so lack of segregation cannot be assessed.
Rule
BS4 Strong requires phenotype-positive, genotype-negative first-, second-, or third-degree relatives of the proband; no qualifying relatives are documented.
Evidence considered
The DICER1 VCEP BS4 rule requires phenotype-positive, genotype-negative first-, second-, or third-degree relatives of the proband and specifies Strong strength.
No non-segregating affected relatives or other BS4-qualifying family data are documented in the consolidated case-evidence bundle.
Still missing
Phenotype-positive first-, second-, or third-degree relatives
Validated genotype results showing those relatives are negative for the variant
Information excluding phenocopies or another pathogenic variant as an explanation for the phenotype
BP2Not assessed: no second pathogenic DICER1 variant or cis/trans phase observation was available.
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Reasoning
The DICER1 VCEP BP2 rule requires at least one observation of the evaluated variant in trans with a pathogenic/likely pathogenic DICER1 variant, or at least three observations in cis or with phase unknown involving two or more different pathogenic/likely pathogenic DICER1 variants. The supplied case-evidence bundle contains no affected-proband or other individual-level observations establishing a second P/LP DICER1 variant, cis/trans phase, or phase-unknown observation meeting the threshold. The variant's ClinVar and population records do not provide BP2 allelic evidence.
Rule
≥1 observation in trans with P/LP DICER1 variant or ≥3 observations in cis or phase unknown with 2+ different P/LP DICER1 variants.
Evidence considered
The DICER1 VCEP specifies BP2 Supporting for at least one observation in trans with a P/LP DICER1 variant, or at least three observations in cis or phase unknown with two or more different P/LP DICER1 variants.
The consolidated case-evidence bundle provides no qualifying phase, affected-proband, or second-variant observation for this case.
Still missing
Individual-level cases with the evaluated variant and a second P/LP DICER1 variant
Validated cis/trans or phase-unknown information
Number of qualifying observations and affected-proband status
Not applicable · 11· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: a synonymous substitution creates no null allele, and SpliceAI predicts no splice effect (max delta 0.00).
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Reasoning
NM_177438.3:c.4014G>A is a synonymous substitution (NP_803187.1:p.(Ala1338=)) that does not create a nonsense, frameshift, canonical +/-1,2 splice-consensus, initiation-codon, or multi-exon-deletion change. The DICER1 VCEP (CSPEC v1.4) PVS1 specification, adapted from Tayoun et al. 2018 SVI recommendations, applies only to nonsense/frameshift variants (assessed against the p.Pro1850 NMD cutoff) and canonical splice-donor/acceptor variants (with exon-specific strength modifiers). This variant falls into neither category, so PVS1 cannot be applied. The generic PVS1 variant assessment scaffold independently confirms the variant does not fall into any generic PVS1 null-variant bucket (nonsense, frameshift, canonical splice). SpliceAI (max delta score = 0.00) shows no evidence of a cryptic/de novo splice effect that could reclassify this as a splice-altering null variant.
Rule
DICER1 VCEP CSPEC v1.4 PVS1 (adapted from ClinGen SVI Tayoun et al. 2018)
Evidence considered
Case summary normalization: protein_3l = NP_803187.1:p.(Ala1338=), a synonymous change with no amino-acid alteration.
DICER1 VCEP CSPEC v1.4 PVS1 rule: applies only to nonsense/frameshift variants (relative to NMD cutoff at p.Pro1850) and canonical +/-1,2 splice-donor/acceptor variants; no branch covers synonymous substitutions.
pvs1_variant_assessment.json: consequence_class = synonymous, canonical_splice_consensus = false, variant_bucket = other, apply_generic_pvs1_framework = false, with rationale that the variant does not fall into any generic PVS1 null-variant bucket.
pvs1_gene_context.json confirms DICER1 LOF is an established germline disease mechanism (lof_mechanism_supported = true), but gene-level LOF eligibility does not itself trigger PVS1 for a variant whose consequence class is not null.
SpliceAI evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00),' ruling out a cryptic-splice-induced null mechanism.
PS1N/ANot applicable: the variant is synonymous (p.(Ala1338=)), so there is no amino acid change to compare against a pathogenic missense.
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Reasoning
NM_177438.3:c.4014G>A produces NP_803187.1:p.(Ala1338=), a synonymous change (no amino acid substitution). The DICER1 VCEP PS1 rule is scoped to 'same AA change' comparisons between missense variants (and separately to non-canonical intronic splicing variants at the same nucleotide); it is not framed to apply to a synonymous variant, since there is no amino acid change to compare against a pathogenic missense variant. No canonical or non-canonical splice-site data support any alternate PS1 pathway here.
Rule
cspec_DICER1_v1.4_PS1
Evidence considered
cspec DICER1 VCEP v1.4 PS1 rule requires a same-amino-acid-change comparison to a variant asserted pathogenic by the ClinGen DICER1 VCEP, or a same-nucleotide comparison for non-canonical intronic splicing variants; neither pathway applies to a synonymous coding variant with no amino acid change.
Still missing
No RNA/splicing functional data available to consider under any adjacent intronic-nucleotide PS1 pathway, though this variant is exonic, not intronic.
PM1N/ANot applicable: PM1 is limited to missense variants at metal-binding or RNase IIIb hotspot codons; this variant is synonymous at residue 1338.
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Reasoning
PM1 in the DICER1 VCEP framework applies only to 'putative missense variants' at the metal ion-binding hotspot codons (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813) or elsewhere within the RNase IIIb domain (p.Y1682-p.S1846). This variant, p.(Ala1338=), is synonymous (not missense) and residue 1338 falls well outside the RNase IIIb domain boundaries, so neither the moderate metal-binding-codon tier nor the supporting RNase IIIb-domain tier is met.
Rule
cspec_DICER1_v1.4_PM1
Evidence considered
cspec DICER1 VCEP v1.4 PM1 rule restricts application to missense variants at the seven metal ion-binding hotspot codons or elsewhere within the RNase IIIb domain (p.Y1682-p.S1846); residue 1338 is outside this domain and the variant is synonymous, not missense.
PM3VCEPNot applicable: the DICER1 VCEP specification designates PM3 as not applicable for this gene.
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Reasoning
The ClinGen DICER1 and miRNA-Processing Gene Expert Panel specification, version 1.4, explicitly designates PM3 as not applicable for DICER1. No PM3 evidence is therefore assigned, regardless of the absence of case-level phase or affected-proband observations in the supplied bundle.
VCEP rule
Not Applicable
Evidence considered
The DICER1 VCEP specification lists PM3 as Not Applicable.
PM4N/ANot applicable: PM4 requires an in-frame indel, and this single-nucleotide synonymous substitution changes no protein length.
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Reasoning
The DICER1 VCEP CSPEC v1.4 PM4 rule is restricted to in-frame indels, applying Moderate strength for in-frame indels affecting a residue within the RNase IIIb domain (p.Y1682-p.S1846) and Supporting strength for in-frame indels outside that domain and outside the specified repeat regions (p.D606-p.D609; p.E1418-p.E1420; p.E1422-p.E1425). NM_177438.3:c.4014G>A is a single-nucleotide substitution producing a synonymous change (p.(Ala1338=)) with no insertion or deletion of residues and therefore no change in protein length. PM4 cannot apply to a variant with no protein-length alteration.
Rule
DICER1 VCEP CSPEC v1.4 PM4
Evidence considered
DICER1 VCEP CSPEC v1.4 PM4 rule text explicitly scoped to 'in-frame indels' within/outside the RNase IIIb domain and named repeat regions (p.D606-p.D609; p.E1418-p.E1420; p.E1422-p.E1425).
Case summary normalization shows the variant is a synonymous single-nucleotide substitution (p.(Ala1338=)), i.e. no in-frame indel and no protein length change, so the PM4 condition is not met.
PM5N/ANot applicable: PM5 compares missense changes at the same residue; this synonymous variant creates no amino acid substitution.
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Reasoning
PM5 in the DICER1 VCEP framework compares the 'missense variant under evaluation' by Grantham score to a different missense change at the same residue already classified pathogenic by the DICER1 VCEP. Because c.4014G>A produces a synonymous change, p.(Ala1338=), there is no amino acid substitution to score against a comparator missense variant, so the criterion's missense-variant precondition is not met.
Rule
cspec_DICER1_v1.4_PM5
Evidence considered
cspec DICER1 VCEP v1.4 PM5 rule is explicitly scoped to 'missense variant under evaluation' with Grantham-score comparison to another pathogenic missense change at the same codon; this variant is synonymous.
pm5_candidates_summary in the case bundle recorded eligible_for_classic_pm5_search=false with recommendation level not_applicable because the variant consequence class (synonymous) is not missense.
Still missing
pm5_candidates.json (pm5_candidates_summary in the bundle) explicitly flags eligible_for_classic_pm5_search=false because the variant consequence class is synonymous, not missense; no comparator search was warranted or performed.
PM6VCEPNot applicable: the DICER1 VCEP directs de novo evidence to PS2, so PM6 is unused.
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Reasoning
PM6 is explicitly not applicable under the DICER1 VCEP specification. The Expert Panel directs evaluators to use PS2 instead of PM6 for de novo evidence, including cases with incomplete parental confirmation.
VCEP rule
Not applicable under the DICER1 VCEP; use PS2 instead of PM6 for de novo evidence.
Evidence considered
The DICER1 VCEP specification marks PM6 as not applicable and instructs: combine de novo evidence with PS2 and use PS2 instead of PM6.
PP2VCEPNot applicable: the DICER1 VCEP defines no PP2 missense-constraint rule for this gene.
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Reasoning
The DICER1 VCEP specification explicitly designates PP2 as Not Applicable for this gene (no missense-constraint-based PP2 rule was defined in the DICER1 cspec), independent of this variant's synonymous nature.
VCEP rule
cspec_DICER1_v1.4_PP2
Evidence considered
cspec DICER1 VCEP v1.4 lists PP2 with applicability: Not Applicable, meaning the DICER1 gene-specific framework does not use this criterion at all.
BP1VCEPNot applicable: the DICER1 VCEP defines no BP1 rule for this gene.
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Reasoning
The DICER1 VCEP specification explicitly designates BP1 as Not Applicable for this gene (no benign missense-in-mechanism-mismatch rule was defined in the DICER1 cspec), independent of this variant's synonymous nature.
VCEP rule
cspec_DICER1_v1.4_BP1
Evidence considered
cspec DICER1 VCEP v1.4 lists BP1 with applicability: Not Applicable, meaning the DICER1 gene-specific framework does not use this criterion at all.
BP3VCEPNot applicable: the DICER1 VCEP marks BP3 unused, and this variant is not an in-frame indel.
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Reasoning
The DICER1 VCEP CSPEC v1.4 explicitly marks BP3 as 'Not Applicable' for this gene (no BP3 rule is specified in the panel's framework), overriding the generic ACMG BP3 (in-frame indel in a repetitive region without a known function) which in any case would not apply here since this variant is a synonymous substitution, not an in-frame indel.
VCEP rule
DICER1 VCEP CSPEC v1.4 BP3 (Not Applicable)
Evidence considered
DICER1 VCEP CSPEC v1.4 lists BP3 with applicability 'Not Applicable', so the gene-specific framework precludes use of this criterion for DICER1 variants.
Independently, the variant is a synonymous substitution with no in-frame indel, so even the generic ACMG BP3 definition (in-frame indel/deletion in a repetitive region of no known functional significance) would not be met.
BP5VCEPNot applicable: the DICER1 VCEP prohibits BP5 given the broad DICER1-related neoplasm spectrum.
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Reasoning
The DICER1 VCEP specifies that BP5 should not be used because of the broad DICER1-related neoplasm spectrum and insufficient evidence that another high-penetrance germline variant would explain such neoplasms.
VCEP rule
DICER1 VCEP v1.4: BP5 not applicable; do not use.
Evidence considered
The DICER1 VCEP marks BP5 not applicable and states that this rule should not be used at this time given the broad spectrum of DICER1-related neoplasms and lack of evidence for alternate high-penetrance germline explanations.
AF 0.0013 · 2039 / 1,614,180 alleles · 6 hom · FAF 0.0014
European (Finnish)271 / 64,026
0.00421 hom
European (non-Finnish)1666 / 1,180,028
0.00145 hom
Remaining individuals59 / 62,506
0.00094
African/African American26 / 75,044
0.00035
Middle Eastern2 / 6,062
0.00033
Admixed American14 / 60,028
0.00023
East Asian1 / 44,886
2.2e-05
0 alternate alleles recorded in 3 other groups: Amish, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.0011 · 322 / 282,384 alleles · 2 hom · FAF 0.0026
European (Finnish)96 / 25,124
0.00381 hom
European (non-Finnish)198 / 128,976
0.00151 hom
Remaining individuals6 / 7,208
0.00083
African/African American10 / 24,704
0.0004
Admixed American11 / 35,436
0.00031
South Asian1 / 30,614
3.3e-05
0 alternate alleles recorded in 2 other groups: Ashkenazi Jewish, East Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD 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.
gnomAD 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.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0009233108842059526, 17/18412 alleles, homozygotes = 0).
BP4SupportingMet (supporting): SpliceAI predicts no splice effect (max delta 0.004). Flagged for human review: MaxEntScan concordance is not yet confirmed.
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Reasoning
The DICER1 VCEP (CSpec v1.4) BP4 rule for synonymous/intronic/non-coding variants requires concordance of MaxEntScan and SpliceAI predicting no splicing effect. SpliceAI predicts a negligible splice impact for this variant (DS_AG=0.002, DS_AL=0.002, DS_DG=0.002, DS_DL=0.004; max delta=0.004), which is an unambiguous null/no-effect result. MaxEntScan output was not present anywhere in this case's evidence bundle, so the two-tool concordance specified by the VCEP text could not be independently confirmed from a second predictor; BP4 is applied at Supporting strength based on the single available, strongly negative SpliceAI signal, flagged for human confirmation of MaxEntScan concordance.
Rule
DICER1 VCEP CSpec v1.4 BP4: for synonymous/intronic/non-coding variants, concordance of MaxEntScan and SpliceAI predicting no splicing effect.
Evidence considered
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.
Still missing
MaxEntScan splice score was not present in the evidence bundle (prefetch.json/evidence.json only contain SpliceAI); the DICER1 VCEP BP4 rule for synonymous variants specifies concordance of MaxEntScan AND SpliceAI, so full two-tool concordance could not be independently verified from the available evidence.
BP7SupportingMet (supporting): silent variant p.(Ala1338=) qualifies under the VCEP BP7 rule, contingent on BP4.
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Reasoning
NM_177438.3:c.4014G>A is a silent (synonymous) variant, NP_803187.1:p.(Ala1338=), which meets the DICER1 VCEP BP7 rule ('Silent variant'). The VCEP BP7 rule carries the explicit caveat that the variant must meet BP4 to apply BP7; BP4 (Supporting) was applied above based on a strongly negative SpliceAI signal (max delta score = 0.004), though full two-predictor (MaxEntScan+SpliceAI) concordance could not be independently confirmed since MaxEntScan data was not present in this case's evidence bundle. BP7 Supporting is therefore applied conditional on that same caveat, flagged for human review.
Rule
DICER1 VCEP CSpec v1.4 BP7: silent variant (or qualifying intronic/non-coding variant), applicable only if BP4 is also met.
Evidence considered
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).
Still missing
BP7 application is contingent on the BP4 caveat, which itself carries an unresolved gap: MaxEntScan splice score was not available to confirm two-tool concordance alongside SpliceAI.
PP3Not met: SpliceAI max delta 0.004 is far below any splice-disruption threshold; REVEL does not apply to this synonymous variant.
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Reasoning
NM_177438.3:c.4014G>A is a synonymous variant (NP_803187.1:p.(Ala1338=)); REVEL is not applicable since the variant is not missense. The DICER1 VCEP (CSpec v1.4) PP3 rule requires either REVEL >= 0.750 for missense variants or predicted splicing effects for splicing/synonymous variants. SpliceAI predicts no significant splice impact for this variant across all four delta-score metrics (DS_AG=0.002, DS_AL=0.002, DS_DG=0.002, DS_DL=0.004; max delta=0.004), far below any threshold consistent with splice disruption. There is no in-silico signal supporting a pathogenic splicing effect, so PP3 is not met.
Rule
DICER1 VCEP CSpec v1.4 PP3: missense REVEL>=0.750 OR splicing predictor agreement predicting splicing effects; for splicing-relevant variants, concordance of MaxEntScan and SpliceAI.
Evidence considered
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 - no significant splice impact predicted (source: spliceai in source_registry).
DICER1 VCEP (ClinGen, CSpec v1.4) PP3 rule: 'For missense variants, REVEL score >= 0.750 OR agreement in splicing predictors predict splicing effects. For splicing variants, concordance of MaxEntScan and SpliceAI.' (source: cspec)
Variant is synonymous (NP_803187.1:p.(Ala1338=)), so the missense REVEL threshold does not apply; REVEL score of 0.371 reported in evidence.json is not relevant to a synonymous change and was not used for PP3.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.371.
5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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.
Richards S et al. · 2015
ACMG/AMP standards and guidelines paper; general nomenclature and evidence-integration guidance only, no DICER1-specific or variant-specific functional assay data.
Clinical reports should include sequence reference(s) to ensure unambiguous naming of the variant at the DNA level as well as provide coding and protein nomenclature to assist in functional interpretations (e.g., “g.” for genomic sequence, “c.” for coding DNA sequence, “p.” for protein, “m.” for mitochondria, etc.).
General Considerations, Nomenclature
Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma.
de Kock L et al. · 2017
Sarcoma cohort sequencing study describing the classic DICER1 germline/somatic two-hit paradigm (germline predisposing variant plus a somatic RNase IIIb hotspot missense mutation); does not mention c.4014G>A and reports no functional splicing or cleavage assay for this variant.
Genetically, DICER1 syndrome-associated tumours are most often characterised by a predisposing germline DICER1 mutation that inactivates one allele, coupled with a highly distinctive second somatic missense mutation affecting one of the RNase IIIb metal ion-binding sites on the other allele (Foulkes et al, 2014).
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.
Hampel H et al. · 2015
General practice guideline on referral indications for cancer predisposition assessment; does not mention DICER1 or c.4014G>A, and contains no functional/RNA/cleavage assay data.
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= 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.
gnomAD 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.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0009233108842059526, 17/18412 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Benign (6 clinical laboratories) and as Likely benign (5 clinical laboratories). (ClinVarID = 221087)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.371.
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58617078, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 7.1.5.
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