About DICER1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
DICER1 c.1282G>C, p.(Glu428Gln)
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 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.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_177438.2:c.1282G>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with allele frequency < 0.000005, meeting the DICER1 VCEP PM2_Supporting threshold.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
The DICER1 VCEP BP4 rule requires REVEL < 0.500 and agreement in splicing predictors that no splicing effects are predicted. REVEL is 0.186 (< 0.500) and SpliceAI predicts no splicing impact (max delta = 0.00). BayesDel (-0.262) also supports a benign computational profile.
Recorded classification: Uncertain significance
ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.4 v1.4 point-based framework: PM2 supporting (+1) + BP4 supporting (-1) = 0 points, 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. DICER1, an endoribonuclease, is altered in various cancer types.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV100602630, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen DICER1 VCEP v1.4, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 7 not met · 8 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_177438.2:c.1282G>C (p.Glu428Gln) is a missense variant in exon 8 of DICER1, located in the N-terminal DExD helicase domain, outside the RNase IIIb domain and metal ion-binding hotspot residues.
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the DICER1 VCEP PM2_Supporting criterion (AF < 0.000005).
Computational evidence suggests a benign effect: REVEL score is 0.186 (< 0.500), BayesDel score is -0.262, and SpliceAI predicts no splicing impact (max delta = 0.00), meeting the DICER1 VCEP BP4_Supporting criterion.
The variant has been observed once in somatic cancers (COSMIC COSV100602630) but has not been reported in ClinVar or the germline literature.
No functional data, de novo observations, family segregation data, or tumor sequencing data are available to assess PS3, PS2, PP1, or PP4.
Under the DICER1 VCEP v1.4 Tavtigian point-based system: PM2_Supporting (+1) + BP4_Supporting (-1) = 0 points, classifying this variant as a Variant of Uncertain Significance.
No criteria match.
Met · 2
PM2 SupportingNM_177438.2:c.1282G>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with allele frequency < 0.000005, meeting the DICER1 VCEP PM2_Supporting threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes).
- Absent from gnomAD-Canada v1.0.
- AF < 0.000005 meets VCEP PM2_Supporting rule.
Sources
BP4 SupportingThe DICER1 VCEP BP4 rule requires REVEL < 0.500 and agreement in splicing predictors that no splicing effects are predicted. REVEL is 0.186 (< 0.500) and SpliceAI predicts no splicing impact (max delta = 0.00). BayesDel (-0.262) also supports a benign computational profile. Details ▾Hide ▴
Evidence considered
- REVEL score 0.186 (< 0.500 threshold).
- SpliceAI max delta 0.00 (no splicing effect).
- BayesDel score -0.262 (benign-leaning).
Sources
Not met · 7 · evaluated, threshold not reached
PS1 PS1 requires a different nucleotide change resulting in the same amino acid substitution (p.Glu428Gln) classified as pathogenic by the ClinGen DICER1 VCEP. The variant is absent from ClinVar, and no pathogenic variant at p.Glu428 has been identified. Details ▾Hide ▴
PS3 No functional data exist for NM_177438.2:c.1282G>C. SpliceAI predicts no splicing impact (max delta = 0.00), and no RNA assay or in vitro cleavage assay data have been reported. The variant is absent from the literature. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.00 — no splicing effect predicted.
- OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence.
Still missing
- No functional assay data (RNA or cleavage) available for this variant.
Sources
PM1 The DICER1 VCEP defines PM1 for missense variants at metal ion-binding residues (p.S1344, E1705, D1709, D1713, G1809, D1810, E1813; moderate) or within the RNase IIIb domain (p.Y1682–S1846; supporting). p.Glu428 is located in the N-terminal DExD helicase domain, far outside both PM1-eligible regions. Details ▾Hide ▴
Evidence considered
- Residue p.E428 is not a VCEP-defined PM1 metal ion-binding residue and is outside the RNase IIIb domain (p.Y1682-S1846).
Sources
PM5 PM5 requires a different missense variant at the same residue (p.Glu428) classified as pathogenic by the ClinGen DICER1 VCEP. No such comparator exists — the variant is absent from ClinVar and no other missense change at p.Glu428 has been identified. Details ▾Hide ▴
PP3 The DICER1 VCEP requires REVEL ≥ 0.750 for PP3_Supporting in missense variants. The REVEL score for NM_177438.2:c.1282G>C is 0.186, well below the threshold. SpliceAI predicts no splicing impact (max delta = 0.00), and BayesDel (-0.262) also supports a benign computational profile. Details ▾Hide ▴
Evidence considered
- REVEL score 0.186 (< 0.750 threshold).
- BayesDel score -0.262 (benign-leaning).
- SpliceAI max delta 0.00 (no splicing effect).
Sources
BA1 BA1 requires allele frequency > 0.003 (0.3%) in gnomAD subpopulations with >2,000 alleles tested and ≥5 alleles present. NM_177438.2:c.1282G>C is absent from all gnomAD versions (v2.1, v4.1, Canada). Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada.
- Allele frequency is 0
- far below the BA1 threshold of >0.3%.
Sources
BS1 BS1 requires allele frequency > 0.0003 (0.03%) in gnomAD subpopulations with >2,000 alleles tested and ≥5 alleles present. NM_177438.2:c.1282G>C is absent from all gnomAD versions. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada.
- Allele frequency is 0
- far below the BS1 threshold of >0.03%.
Sources
Not assessed · 8 · no assessment recorded
PS2 No de novo data are available for this variant. No literature reports, ClinVar submissions, or other sources document de novo occurrence of NM_177438.2:c.1282G>C. Details ▾Hide ▴
Still missing
- No de novo observations identified in any source.
PS4 No clinical phenotype data from unrelated probands are available for this variant. The variant is absent from ClinVar and has not been reported in any published case series or cohorts. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no proband data available.
Still missing
- No proband or phenotype data identified.
Sources
PP1 No cosegregation data are available. No family studies or pedigrees involving NM_177438.2:c.1282G>C have been reported. Details ▾Hide ▴
Still missing
- No family cosegregation data available.
PP4 No somatic tumor testing data are available to evaluate for an RNase IIIb hotspot second hit with retention of the germline variant. PP4 requires tumor sequencing of a DICER1-associated neoplasm in a proband carrying this variant. Details ▾Hide ▴
Still missing
- No tumor sequencing data available for this variant.
BS2 No data are available regarding tumor-free females through age 50 or homozygosity observations for this variant. Details ▾Hide ▴
Still missing
- No BS2-eligible population data available.
BS3 No functional data are available to evaluate a benign effect. The BS3_Strong rule (RNA assay showing no splicing impact) is restricted to intronic or synonymous variants. The BS3_Supporting rule requires an in vitro cleavage assay demonstrating normal 5p/3p miRNA production, which has not been performed for this variant. Details ▾Hide ▴
Evidence considered
- No functional assay data (RNA or cleavage) available.
- BS3_Strong restricted to intronic/synonymous variants
- BS3_Supporting requires cleavage assay not performed.
Still missing
- No cleavage assay data available for this missense variant.
Sources
BS4 No family segregation data are available. BS4 requires phenotype-positive, genotype-negative first-, second-, or third-degree relatives of the proband. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP2 No data are available regarding observations of this variant in trans with a known P/LP DICER1 variant or in cis/phase unknown with multiple P/LP DICER1 variants. Details ▾Hide ▴
Still missing
- No phase data available for this variant.
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice sites). NM_177438.2:c.1282G>C is a missense variant (p.Glu428Gln) and is outside the scope of the DICER1 VCEP PVS1 rules. Details ▾Hide ▴
Evidence considered
- VCEP DICER1 v1.4 PVS1 rule: restricted to nonsense
- frameshift
- and canonical splice variants only.
Sources
PM3 VCEPDICER1-related tumor predisposition is autosomal dominant; PM3 (detected in trans for recessive disorders) is not applicable per the VCEP. Details ▾Hide ▴
Evidence considered
- DICER1 VCEP v1.4: PM3 Not Applicable (autosomal dominant inheritance).
Sources
PM4 N/APM4 applies to in-frame indels and stop-loss variants; this is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPPM6 is not applicable under the DICER1 VCEP; de novo evidence is assessed exclusively through PS2. Details ▾Hide ▴
PP2 VCEPPP2 is not applicable under the DICER1 VCEP. Although DICER1 meets the missense constraint z-score threshold, the VCEP recommends against using PP2 due to the presence of multiple benign/likely benign missense variants in ClinVar. Details ▾Hide ▴
PP5 VCEPPP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The DICER1 VCEP marks PP5 as Not Applicable. Details ▾Hide ▴
BP1 VCEPBP1 is not applicable to DICER1 under the VCEP. Truncating variants account for only a portion of disease-causing variants in DICER1. Details ▾Hide ▴
BP3 VCEPBP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP5 VCEPBP5 is not applicable to DICER1 under the VCEP. Given the broad spectrum of DICER1-related neoplasms and the lack of evidence for other high-penetrance germline variants that could account for such neoplasms, this rule should not be used. Details ▾Hide ▴
BP6 VCEPBP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The DICER1 VCEP marks BP6 as Not Applicable. Details ▾Hide ▴
BP7 N/ABP7 applies to silent/intronic/non-coding variants and requires the variant also meet BP4. NM_177438.2:c.1282G>C is a missense variant (p.Glu428Gln) and does not fall into any BP7-eligible variant class. Details ▾Hide ▴
Evidence considered
- VCEP DICER1 v1.4 BP7 rule: restricted to silent/intronic/non-coding variants. Missense variant is outside scope.
Sources
PS5 N/APS5 is not defined in the ClinGen DICER1 VCEP v1.4 criteria set. Details ▾Hide ▴
Identifiers
- Gene
- DICER1
- Transcript
- NM_177438.2
- Coding (HGVS c.)
- NM_177438.2:c.1282G>C
- Protein (HGVS p.)
- NP_803187.1:p.(Glu428Gln)
- GRCh38
- chr14:95124290 C>G
- GRCh37
- chr14:95590627 C>G
- COSMIC
- COSV100602630
Gene diagram
Every interpreted variant in DICER1, mapped onto the exon structure of NM_177438.2. Select a row to find it on the plot.
DICER1NM_177438.2
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 DICER1
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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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.186
- BayesDel
- -0.263
How the predictions were used
BP4 SupportingThe DICER1 VCEP BP4 rule requires REVEL < 0.500 and agreement in splicing predictors that no splicing effects are predicted. REVEL is 0.186 (< 0.500) and SpliceAI predicts no splicing impact (max delta = 0.00). BayesDel (-0.262) also supports a benign computational profile. Details ▾Hide ▴
Evidence considered
- REVEL score 0.186 (< 0.500 threshold).
- SpliceAI max delta 0.00 (no splicing effect).
- BayesDel score -0.262 (benign-leaning).
Sources
PP3 The DICER1 VCEP requires REVEL ≥ 0.750 for PP3_Supporting in missense variants. The REVEL score for NM_177438.2:c.1282G>C is 0.186, well below the threshold. SpliceAI predicts no splicing impact (max delta = 0.00), and BayesDel (-0.262) also supports a benign computational profile. Details ▾Hide ▴
Evidence considered
- REVEL score 0.186 (< 0.750 threshold).
- BayesDel score -0.262 (benign-leaning).
- SpliceAI max delta 0.00 (no splicing effect).
Sources
BP7 N/ABP7 applies to silent/intronic/non-coding variants and requires the variant also meet BP4. NM_177438.2:c.1282G>C is a missense variant (p.Glu428Gln) and does not fall into any BP7-eligible variant class. Details ▾Hide ▴
Evidence considered
- VCEP DICER1 v1.4 BP7 rule: restricted to silent/intronic/non-coding variants. Missense variant is outside scope.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.186. BayesDel score = -0.262519.
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243094
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_177438.2%3Ac.1282G%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/14-95590627-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr14-95124290-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/14-95124290-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_177438.2%3Ac.1282…
- OncoKB ↗www.oncokb.org/gene/DICER1/E428Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=188101746
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.186. BayesDel score = -0.262519.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. DICER1, an endoribonuclease, is altered in various cancer types.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV100602630, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.