Variant classification summary

NM_177438.2:c.4199A>G

DICER1 · NP_803187.1:p.(Asp1400Gly) · NM_177438.2

GRCh37: chr14:95566124 T>C · GRCh38: chr14:95099787 T>C

Gene: DICER1 Transcript: NM_177438.2

Final call

Likely Benign

BP4 supporting BP6 supporting benign

Variant details

Gene

DICER1

Transcript

NM_177438.2

Protein

NP_803187.1:p.(Asp1400Gly)

gnomAD AF

4.712418462759493e-05 (v4.1)

ClinVar

Likely Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_177438.2:c.4199A>G (p.Asp1400Gly) is a missense variant in exon 22 of DICER1.

2

This variant is present in gnomAD v4.1 at an allele frequency of 4.71e-05 (76/1,612,760 alleles, 0 homozygotes), with a grpmax filtering allele frequency of 4.511e-05. It has been observed across multiple subpopulations, including 7 alleles in the South Asian population (AF=7.69e-05). These frequencies exceed the DICER1 VCEP PM2_Supporting threshold of <5e-06.

3

This variant has been reported in ClinVar as Likely Benign following review by the ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel (ClinVar Variation ID: 412173). Individual clinical laboratory submissions include Uncertain Significance (4 laboratories) and Likely Benign (2 laboratories).

4

In silico predictors support a benign interpretation: REVEL score is 0.142, well below the DICER1 VCEP BP4_Supporting threshold of <0.500. SpliceAI predicts no splicing impact (max delta = 0.12). These findings meet BP4_Supporting per DICER1 VCEP criteria.

5

The variant has been observed in two siblings with pleuropulmonary blastoma (Leckey et al. 2019, PMID:30665929). However, both siblings also carried a pathogenic DICER1 splice variant (c.2437-2A>G), and the authors explicitly state that c.4199A>G 'has not been associated with DICER1-associated phenotypic features.' In silico algorithms reportedly suggest the variant 'is likely to be tolerated.' No functional studies have been performed.

6

Residue Asp1400 lies outside the RNase IIIb domain (p.Y1682–S1846) and is not one of the seven metal ion-binding residues defined by the DICER1 VCEP for PM1. No pathogenic variant at the same residue is known for PS1 or PM5 application. No functional, segregation, de novo, or case-control data support application of any pathogenic criterion.

7

Applying the DICER1 VCEP (version 1.4.0) point-based Tavtigian framework: only BP4_Supporting (−1 point) is met. All other applicable criteria are not met. Total point value = −1, which falls within the Uncertain Significance range (Rule 3: ≥−1 and ≤5).

Final determination: 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 yields a total score of -2, which maps to Likely Benign under the specified Tavtigian-style ranges.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_177438.2:c.4199A>G is a missense variant. PVS1 applies only to null variants (nonsense, frameshift, or canonical ±1,2 splice consensus). The DICER1 VCEP PVS1 decision tree does not assign PVS1 to missense substitutions.	vcep_pvs1_decisiontree
PS1	Not met	PS1 requires a different nucleotide change producing the same amino acid substitution (p.Asp1400Gly) that has been classified as pathogenic by the ClinGen DICER1 VCEP. No such variant is known.	clinvar cspec
PS2	Not met	No de novo occurrence data are available for this variant. The DICER1 VCEP uses a de novo points system; no confirmed de novo observations with maternity and paternity confirmation have been reported.	cspec
PS3	Not met	No functional studies (RNA splicing assay or in vitro cleavage assay) have been performed for this variant. In silico predictors (REVEL 0.142, SpliceAI max delta 0.12) suggest no deleterious splicing or functional impact. Per DICER1 VCEP, PS3 requires RNA assay demonstrating splicing impact or cleavage assay failure, neither of which is available.	revel spliceai bayesdel cspec PMID:30665929
PS4	Not met	The DICER1 VCEP uses a phenotype points system for PS4. No case-control study or systematic proband collection demonstrates enrichment of this variant in affected individuals. The variant was observed in two siblings with PPB but both also carried a pathogenic DICER1 splice variant (c.2437-2A>G). Leckey et al. 2019 explicitly states the variant has not been associated with DICER1-associated phenotypic features.	clinvar cspec PMID:30665929
PS5	N/A	PS5 is not defined in the ClinGen DICER1 VCEP specification (version 1.4.0). This criterion is not part of the DICER1 gene-specific framework.	cspec
PM1	Not met	The variant results in p.Asp1400Gly. Residue 1400 is outside the RNase IIIb domain (p.Y1682–S1846) and is not one of the seven metal ion-binding residues (p.S1344, E1705, D1709, D1713, G1809, D1810, E1813) defined by the DICER1 VCEP for PM1 application.	cspec
PM2	Not met	The DICER1 VCEP PM2_Supporting threshold is allele frequency <0.000005 across gnomAD with no more than one allele in any subpopulation. In gnomAD v4.1 (the most comprehensive version), the global allele frequency is 4.71e-05 (76/1,612,760 alleles), exceeding the PM2 threshold approximately 9-fold. The South Asian subpopulation has 7 alleles (AF=7.69e-05), which violates the 'no more than one allele in any subpopulation' requirement.	gnomad_v4 cspec
PM5	Not met	PM5 requires a different missense change at the same residue (D1400) that has been classified as pathogenic by the ClinGen DICER1 VCEP. No such comparator variant was identified in the PM5 candidate search.	pm5_candidates cspec
PM6	N/A	The DICER1 VCEP has opted to drop PM6 and exclusively use PS2 for de novo evidence. PM6 is not independently applied in this framework.	cspec
PP1	Not met	No co-segregation data are available for this variant. The variant was observed in two siblings but both also carry a pathogenic DICER1 splice variant (c.2437-2A>G), confounding segregation analysis. The DICER1 VCEP requires 3–4 meioses for PP1_Supporting.	cspec PMID:30665929
PP2	N/A	The DICER1 VCEP recommends PP2 not be used for DICER1. Although DICER1 meets the missense constraint z-score threshold (4.23 on gnomAD), the VCEP cites the presence of benign (9) and likely benign (30) missense variants throughout the gene in ClinVar as a contraindication.	cspec
PP3	Not met	The DICER1 VCEP requires REVEL score ≥0.750 for PP3_Supporting in missense variants, or agreement in splicing predictors of splicing effects. REVEL score for this variant is 0.142 (far below threshold). SpliceAI max delta is 0.12, indicating no predicted splicing impact. No evidence supports a deleterious in silico prediction.	revel spliceai cspec
PP4	Not met	The DICER1 VCEP PP4 requires somatic tumor testing demonstrating a known RNase IIIb hotspot second hit (at residues S1344, E1705, D1709, D1713, G1809, D1810, or E1813) with retention of the germline variant. No tumor testing data are available. Leckey et al. 2019 explicitly notes: 'the tumour was not tested for hotspot variants, as the family declined additional genetic testing.'	cspec PMID:30665929
PP5	N/A	The DICER1 VCEP states PP5 is not for use, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Not met	BA1 requires allele frequency >0.003 (0.3%) in a gnomAD subpopulation with >2,000 alleles tested and ≥5 alleles present. The highest subpopulation frequency in gnomAD v4.1 is South Asian at 7.69e-05 (0.0077%), far below the BA1 threshold.	gnomad_v4 cspec
BS1	Not met	BS1 requires allele frequency >0.0003 (0.03%) in a gnomAD subpopulation with >2,000 alleles tested and ≥5 alleles present. The highest qualifying subpopulation in gnomAD v4.1 is South Asian (7 alleles, 91,066 alleles, AF=7.69e-05 = 0.0077%), which is below the BS1 threshold of 0.03%.	gnomad_v4 cspec
BS2	Not met	BS2 requires ≥40 unrelated females tumor-free through age 50 (Strong) or ≥10 (Supporting), or homozygosity in healthy individuals. No such data are available for this variant. The gnomAD data show 76 heterozygous carriers in v4.1 but no clinical annotation of tumor status or age is available.	cspec
BS3	Not met	The DICER1 VCEP BS3_Strong requires an RNA assay showing no splicing impact (for intronic/synonymous variants) observed more than once. BS3_Supporting requires an in vitro cleavage assay demonstrating normal 5p and 3p miRNA production. Neither type of functional study has been performed for this variant. Leckey et al. 2019 notes: 'published functional studies have not been done to confirm this.'	cspec PMID:30665929
BS4	Not met	BS4 requires phenotype-positive, genotype-negative 1st–3rd degree relatives. No such family structure data are available. The only family reported (Leckey et al. 2019) shows two affected siblings both carrying the variant, which does not demonstrate lack of segregation.	cspec PMID:30665929
BP1	N/A	The DICER1 VCEP states: 'This rule code does not apply to this gene, as truncating variants account for only a portion of disease-causing variants.'	cspec
BP2	Not met	BP2 requires ≥1 observation in trans with a P/LP DICER1 variant, or ≥3 observations in cis/phase unknown with 2+ different P/LP DICER1 variants. The variant co-occurs with a pathogenic DICER1 splice variant (c.2437-2A>G) in two siblings (Leckey et al. 2019), but phase is unknown. Without confirmed trans configuration, BP2 cannot be applied.	cspec PMID:30665929
BP4	Met	The DICER1 VCEP BP4_Supporting requires REVEL score <0.500 and agreement in splicing predictors that no splicing effects are predicted for missense variants. REVEL score is 0.142 (<0.500 threshold satisfied). SpliceAI max delta is 0.12, indicating no predicted splicing impact. Both conditions are met.	revel spliceai cspec
BP5	N/A	The DICER1 VCEP states: 'Given the broad spectrum of DICER1-related neoplasms and the lack of evidence of other high-penetrance germline variants that could account for such neoplasms, this rule should not be used at this time.'	cspec
BP6	Met	Expert panel ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen classified as Likely benign.	cspec clinvar
BP7	N/A	BP7 applies only to silent (synonymous) variants, intronic variants at or beyond +7/−21 positions, or other non-coding variants. NM_177438.2:c.4199A>G is a missense variant producing p.Asp1400Gly, not qualifying for BP7. Additionally, the VCEP caveat requires BP4 to be met to apply BP7.	cspec
BP3	N/A	Skipped: in-frame indels criterion; not applicable to a substitution variant.
PM3	N/A	Skipped: autosomal recessive criterion; DICER1-related tumor predisposition is autosomal dominant.
PM4	N/A	Skipped: in-frame indel criterion; not applicable to a substitution variant.

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