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DICER1c.5125G>CLikely pathogenic
Print report
Variant interpretation report

DICER1 c.5125G>C, p.(Asp1709His)

NM_177438.2:c.5125G>C NP_803187.1:p.(Asp1709His) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About DICER1

No gene-level summary was recorded for this case.

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 v1.4.0. 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: 4 Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS2Moderate
PS2 · moderate

A confirmed de novo occurrence of NM_177438.2:c.5125G>C (p.Asp1709His) was reported in a child (case 12) with pituitary blastoma, bilateral lung cysts, and bilateral renal cystic masses (de Kock et al. 2014, PMID:24839956). Per DICER1 VCEP PS2 rules, one confirmed de novo observation yields 1 de novo point, meeting the moderate threshold (≥1 but <2 points).

PM1Moderate
PM1 · moderate

p.Asp1709 is one of seven metal ion-binding residues (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813) explicitly defined by the DICER1 VCEP as meeting PM1 at moderate strength. The variant p.Asp1709His alters a critical metal ion-binding residue in the RNase IIIb catalytic domain.

PM2Supporting
PM2 · supporting

NM_177438.2:c.5125G>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. This satisfies the DICER1 VCEP PM2 rule: allele frequency <0.000005 across gnomAD with no more than one allele in any subpopulation.

PP3Supporting
PP3 · supporting

REVEL score is 0.988, which is ≥0.750, meeting the DICER1 VCEP PP3 threshold for missense variants. SpliceAI predicts no splicing impact (max delta = 0.00), consistent with pathogenicity being mediated through the amino acid change rather than altered splicing.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.4.0 v1.4.0 point-based framework: PS2 moderate (+2) + PM1 moderate (+2) + PM2 supporting (+1) + PP3 supporting (+1) = 6 points, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded. ClinVar API review status: criteria provided, single submitter.

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
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen DICER1 VCEP v1.4.0, with the data and sources behind each one.

26 criteria with recorded statuses: 4 met · 12 not met · 0 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_177438.2:c.5125G>C (p.Asp1709His) alters a metal ion-binding residue in the RNase IIIb catalytic domain of DICER1, meeting PM1 at moderate strength per the ClinGen DICER1 VCEP.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength (VCEP threshold: AF <0.000005).

REVEL score of 0.988 exceeds the VCEP PP3 threshold of ≥0.750, with no predicted splicing impact (SpliceAI max delta = 0.00), meeting PP3 at supporting strength.

A confirmed de novo occurrence was reported in an infant with pituitary blastoma, bilateral lung cysts, and bilateral renal cystic masses (de Kock et al. 2014), meeting PS2 at moderate strength (1 de novo point).

Per the DICER1 VCEP Tavtigian point-based system: PM1_Moderate (2) + PM2_Supporting (1) + PP3_Supporting (1) + PS2_Moderate (2) = 6 points, which falls in the Likely Pathogenic range (≥6, ≤9).

Met · 4

PS2 ModerateA confirmed de novo occurrence of NM_177438.2:c.5125G>C (p.Asp1709His) was reported in a child (case 12) with pituitary blastoma, bilateral lung cysts, and bilateral renal cystic masses (de Kock et al. 2014, PMID:24839956). Per DICER1 VCEP PS2 rules, one confirmed de novo observation yields 1 de novo point, meeting the moderate threshold (≥1 but <2 points). Details ▾Hide ▴
Evidence considered
  • Single confirmed de novo observation in case 12 (PMID:24839956): infant with pituitary blastoma
  • multi-focal bilateral lung cysts
  • and bilateral renal cystic masses. The paper explicitly states the mutation is de novo (Fig. 2f).
Still missing
  • Mosaicism could not be excluded by the authors
  • only lymphocyte gDNA available. Parentage confirmation method not detailed.
Sources
PMID:24839956 ↗
PM1 Moderatep.Asp1709 is one of seven metal ion-binding residues (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813) explicitly defined by the DICER1 VCEP as meeting PM1 at moderate strength. The variant p.Asp1709His alters a critical metal ion-binding residue in the RNase IIIb catalytic domain. Details ▾Hide ▴
Evidence considered
  • VCEP explicitly lists p.D1709 as a PM1_Moderate metal ion-binding residue. Cancerhotspots.org confirms this is a statistically significant hotspot residue. PMID:24839956 discusses Asp1709 as a metal ion-binding residue critical for 5p miRNA processing.
Sources
PMID:24839956 ↗
PM2 SupportingNM_177438.2:c.5125G>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. This satisfies the DICER1 VCEP PM2 rule: allele frequency <0.000005 across gnomAD with no more than one allele in any subpopulation. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • absent from gnomAD v4.1 (exomes)
  • absent from gnomAD-Canada v1.0.
Still missing
  • Coverage at this position was not explicitly confirmed
  • assume ≥20x per VCEP requirement.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingREVEL score is 0.988, which is ≥0.750, meeting the DICER1 VCEP PP3 threshold for missense variants. SpliceAI predicts no splicing impact (max delta = 0.00), consistent with pathogenicity being mediated through the amino acid change rather than altered splicing. Details ▾Hide ▴
Evidence considered
  • REVEL score = 0.988 (≥0.750 threshold). SpliceAI max delta = 0.00
  • confirming no cryptic splicing confounder.
Sources
revelspliceai ↗

Not met · 12 · evaluated, threshold not reached

PS1 PS1 requires a different nucleotide change producing the same amino acid change (p.Asp1709His) that is classified as pathogenic by the ClinGen DICER1 VCEP. Asp1709 (GAC) can only become His via a single nucleotide change (G>C at position 5125). No alternative nucleotide variant producing the same Asp1709His change exists, and no VCEP-classified pathogenic comparator was identified. Details ▾Hide ▴
Evidence considered
  • Only one nucleotide change (c.5125G>C) produces p.Asp1709His from the reference codon GAC. No alternative nucleotide variant at this position exists.
PS3 The DICER1 VCEP PS3 rules require variant-specific RNA splicing assay or in vitro cleavage assay data. No variant-specific functional assay (RNA splicing or pre-miRNA cleavage) has been performed for c.5125G>C. The general knowledge that Asp1709 is a metal ion-binding residue in the RNase IIIb domain is captured by PM1; it does not constitute variant-specific functional evidence for PS3. SpliceAI predicts no splicing impact (max delta = 0.00), so no RNA splicing assay is indicated. Details ▾Hide ▴
Evidence considered
  • No variant-specific functional assay data available. SpliceAI max delta = 0.00
  • no splicing impact predicted. Metal-binding residue knowledge applied via PM1
  • not PS3.
Still missing
  • No in vitro cleavage assay or RNA splicing assay data for this specific variant.
Sources
spliceai ↗
PS4 The DICER1 VCEP PS4 rule requires phenotype points from unrelated probands with DICER1-specific phenotypes. While a single proband (case 12) has been reported with this variant and pituitary blastoma, the required phenotype point tabulation and scoring against the VCEP phenotype table cannot be completed from the available data without additional proband summaries. Details ▾Hide ▴
Evidence considered
  • One proband (case 12) with pituitary blastoma reported in PMID:24839956. Insufficient data to tabulate phenotype points per VCEP PS4 table.
Still missing
  • Additional unrelated probands and VCEP phenotype point tabulation needed.
Sources
PMID:24839956 ↗
PM5 The DICER1 VCEP PM5 rule explicitly states it cannot be applied in combination with PM1 or PS1. Since PM1_Moderate is met at this residue (p.D1709 is a metal ion-binding hotspot), PM5 is precluded by VCEP rule. Details ▾Hide ▴
Evidence considered
  • PM1 is met at p.D1709
  • PM5 cannot be applied in combination with PM1 per DICER1 VCEP rule.
PP1 No co-segregation data are available for this variant. The DICER1 VCEP requires 3-4 meioses for supporting, 5-6 for moderate, and ≥7 for strong with affected family members having high/moderate-specificity phenotypes. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • Family segregation data would strengthen this assessment.
BA1 The variant is absent from gnomAD v2.1 and v4.1. The DICER1 VCEP BA1 threshold requires allele frequency >0.003 (0.3%) in gnomAD subpopulations with >2,000 alleles tested and ≥5 alleles present. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • well below BA1 threshold of >0.3%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from gnomAD. The DICER1 VCEP BS1 threshold requires allele frequency >0.0003 (0.03%) in gnomAD subpopulations with >2,000 alleles tested and ≥5 alleles present. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • well below BS1 threshold of >0.03%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No observations of homozygosity and no data on tumor-free adult females through age 50 are available for this variant. Details ▾Hide ▴
Evidence considered
  • No homozygosity observations in gnomAD. No healthy adult female data available.
Still missing
  • Population-level healthy adult data not assessed.
BS3 The DICER1 VCEP BS3 requires functional evidence of no splicing impact or intact pre-miRNA cleavage. No such functional data exist for this variant. The VCEP BS3_Strong is for intronic/synonymous variants with normal RNA splicing; BS3_Supporting requires in vitro cleavage assay showing normal function. Neither applies to this missense variant with no functional assay data. Details ▾Hide ▴
Evidence considered
  • No functional data demonstrating no damaging effect. VCEP BS3 primarily targets intronic/synonymous variants with RNA splicing data.
BS4 No segregation data demonstrating lack of segregation in affected family members are available. The DICER1 VCEP requires phenotype-positive, genotype-negative 1st/2nd/3rd degree relatives of the proband. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • Family segregation data would be needed to assess this criterion.
BP2 No observations of this variant in trans with a pathogenic/likely pathogenic DICER1 variant or in cis with multiple P/LP variants are available. Details ▾Hide ▴
Evidence considered
  • No observations in trans or cis with other P/LP DICER1 variants.
Still missing
  • Phase information with other DICER1 variants not available.
BP4 The DICER1 VCEP BP4 rule for missense variants requires REVEL <0.500 and agreement in splicing predictors of no splicing effect. REVEL score is 0.988, which far exceeds the BP4 threshold. This variant is computationally predicted to be damaging, not benign. Details ▾Hide ▴
Evidence considered
  • REVEL = 0.988
  • above BP4 threshold of <0.500. SpliceAI max delta = 0.00
  • but REVEL score precludes BP4.
Sources
revelspliceai ↗
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_177438.2:c.5125G>C is a missense variant (p.Asp1709His). The DICER1 VCEP PVS1 rules apply only to nonsense, frameshift, and canonical splice site variants. This missense variant does not fall into any PVS1 bucket per the VCEP PVS1 decision tree. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not a null variant. VCEP PVS1 decision tree does not apply to missense substitutions.
Sources
vcep_pvs1_decisiontreepvs1_variant_assessment
PM6 VCEPThe DICER1 VCEP has opted to drop PM6 and exclusively use PS2 for de novo evidence. Details ▾Hide ▴

No further detail was recorded.

PP2 VCEPThe DICER1 VCEP recommends PP2 not be used for DICER1 due to the presence of benign/likely benign missense variants in ClinVar despite the gene meeting the missense constraint z-score cutoff. Details ▾Hide ▴

No further detail was recorded.

PP4 N/AThe DICER1 VCEP explicitly states PP4 is NOT applicable if the germline variant is a missense variant in one of the seven RNase IIIb hotspot codons. p.Asp1709 is one of those seven codons (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813). Details ▾Hide ▴
Evidence considered
  • p.D1709 is an RNase IIIb hotspot codon
  • PP4 explicitly excluded by VCEP for missense variants at these residues.
PP5 VCEPPP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The DICER1 VCEP explicitly marks PP5 as not applicable. Details ▾Hide ▴

No further detail was recorded.

BP1 VCEPThe DICER1 VCEP states BP1 is not applicable because truncating variants account for only a portion of disease-causing variants in DICER1; missense variants are a common mechanism of disease. Details ▾Hide ▴

No further detail was recorded.

BP5 VCEPThe DICER1 VCEP states BP5 is not applicable due to the broad spectrum of DICER1-related neoplasms and lack of evidence of other high-penetrance germline variants that could account for such phenotypes. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPBP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The DICER1 VCEP explicitly marks BP6 as not applicable. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_177438.2:c.5125G>C is a missense variant, not a silent/synonymous or intronic variant. BP7 applies only to silent variants or intronic variants at or beyond +7 to -21 positions. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is for synonymous/intronic variants.
PS5 N/APS5 is not a criterion defined by the DICER1 VCEP framework or the standard ACMG/AMP 2015 criteria. The counterpart PP5 is explicitly not applicable for this VCEP. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
DICER1
Transcript
NM_177438.2
Coding (HGVS c.)
NM_177438.2:c.5125G>C
Protein (HGVS p.)
NP_803187.1:p.(Asp1709His)
GRCh38
chr14:95094127 C>G
GRCh37
chr14:95560464 C>G
ClinVar
932993

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…
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

SpliceAI acceptor lossat +18 bp
0.000
SpliceAI acceptor gainat +94 bp
0.000
SpliceAI donor lossat -127 bp
0.000
SpliceAI donor gainat +143 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.988
BayesDel
0.504

How the predictions were used

PP3 SupportingREVEL score is 0.988, which is ≥0.750, meeting the DICER1 VCEP PP3 threshold for missense variants. SpliceAI predicts no splicing impact (max delta = 0.00), consistent with pathogenicity being mediated through the amino acid change rather than altered splicing. Details ▾Hide ▴
Evidence considered
  • REVEL score = 0.988 (≥0.750 threshold). SpliceAI max delta = 0.00
  • confirming no cryptic splicing confounder.
Sources
revelspliceai ↗
BP4 The DICER1 VCEP BP4 rule for missense variants requires REVEL <0.500 and agreement in splicing predictors of no splicing effect. REVEL score is 0.988, which far exceeds the BP4 threshold. This variant is computationally predicted to be damaging, not benign. Details ▾Hide ▴
Evidence considered
  • REVEL = 0.988
  • above BP4 threshold of <0.500. SpliceAI max delta = 0.00
  • but REVEL score precludes BP4.
Sources
revelspliceai ↗
BP7 N/ANM_177438.2:c.5125G>C is a missense variant, not a silent/synonymous or intronic variant. BP7 applies only to silent variants or intronic variants at or beyond +7 to -21 positions. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is for synonymous/intronic variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.988. BayesDel score = 0.503763.

3 paper records listed. 1 cited in the classification.

Cited in the classification

  • Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations.
    de Kock L et al. · 2014 Jul
    Reports NM_177438.2:c.5125G>C (p.Asp1709His) as a de novo germline mutation in an infant (case 12) with pituitary blastoma, extensive multi-focal bilateral lung cysts, and bilateral renal cystic masses. The somatic second hit was loss of the wild-type allele (LOH). Asp1709 is a metal ion-binding residue in the RNase IIIb domain; mutations at such residues reduce 5p miRNA processing, shifting expression toward 3p-derived miRNAs.
    → PS2 → PM1 Names this variant
    PMID 24839956 ↗
    Source detail
    The de novo mutation, c.5125G>C [p.(Asp1709His)], is the third reported DICER1 mutation in lymphocyte gDNA affecting a metal ion-binding residue within an RNase III domain [9].

    Location Discussion, paragraph on case 12; Results, final paragraph; Table 1 and Fig. 5

    Context Germline DNA from blood lymphocytes; tumor DNA from FFPE pituitary blastoma. Sanger sequencing confirmation. LOH of wild-type allele in tumor confirmed by comparing germline and tumor gDNA peak ratios.

Other 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
    This is the ACMG/AMP 2015 standards and guidelines for variant interpretation. It provides the general framework for criteria combination but does not mention NM_177438.2:c.5125G>C or any DICER1-specific variant.
    Does not name this variant
    PMID 25741868 ↗
  • DICER1-Related Tumor Predisposition.
    Adam MP et al. · 1993
    GeneReviews entry for DICER1-related tumor predisposition. The abstract and full text were not available for review. No evidence that this specific variant is discussed.
    Does not name this variant
    PMID 24761742 ↗

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

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 has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 932993)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.988. BayesDel score = 0.503763.

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 lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant lies in a statistically significant hotspot.