Variant classification summary

NM_177438.3:c.4206+11_4206+13del

DICER1 · NP_803187.1:p.? · NM_177438.3

GRCh37: chr14:95566103 ACAC>A · GRCh38: chr14:95099766 ACAC>A

Gene: DICER1 Transcript: NM_177438.3

Final call

Likely Benign

BS1 strong BS2 supporting

Variant details

Gene

DICER1

Transcript

NM_177438.3

Protein

NP_803187.1:p.?

gnomAD AF

0.0004390120246809728 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS1 (Strong): gnomAD v4.1 East Asian allele frequency 0.00261 (76/29,110 alleles) exceeds the >0.0003 threshold.

2

BS2 (Supporting): gnomAD v4.1 reports 2 homozygotes overall, meeting the VCEP rule for homozygous observations without clinical information.

3

Final classification: Likely Benign, from -5 points (BS1 Strong -4, BS2 Supporting -1) within the -6 to -2 range of the DICER1 VCEP point-based framework.

Final determination: Under the DICER1 VCEP v1.4 Tavtigian point-based framework, a total score from -6 through -2 is classified as Likely Benign.

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	Not met	Not met: this deep intronic deletion has no predicted splice impact (SpliceAI max delta 0.012), so no loss-of-function consequence is established.	cspec spliceai pvs1_variant_assessment vcep_pvs1_decisiontree
PS1	Not assessed	Not assessed: no ClinGen DICER1 VCEP pathogenic comparator at this nucleotide was available.	cspec spliceai
PS2	Not assessed	Not assessed: no parental testing, de novo assertion, or de novo point data were available.	cspec
PS3	Not assessed	Not assessed: no validated functional study, RNA assay, or cleavage-assay data were available for this variant.	cspec
PS4	Not assessed	Not assessed: no affected probands, phenotype points, or case-control data for this exact variant were available.	cspec
PM1	N/A	Not applicable: the VCEP limits PM1 to missense variants in the RNase IIIb domain; this intronic deletion has no assignable residue.	cspec
PM2	Not met	Not met: gnomAD v4.1 total AF 0.000439 (620/1,412,262 alleles) far exceeds the <0.000005 Supporting threshold.	cspec gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: the DICER1 VCEP designates PM3 as not applicable because the disorder is autosomal dominant.	cspec
PM4	Not met	Not met: this intronic 3-bp deletion has no assigned protein consequence, so no in-frame indel or RNase IIIb residue can be evaluated.	cspec spliceai
PM5	N/A	Not applicable: PM5 requires a missense variant with a VCEP-pathogenic comparator at the same residue; this is intronic with no same-residue candidates.	cspec pm5_candidates
PM6	N/A	Not applicable: the DICER1 VCEP explicitly marks PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no affected or genotype-positive relatives, pedigree, or meiosis count were available.	cspec
PP2	N/A	Not applicable: the DICER1 VCEP designates PP2 as not applicable, and this variant is intronic rather than missense.	cspec
PP3	Not assessed	Not assessed: SpliceAI max delta 0.012 does not support a splice effect, and no MaxEntScan result was available.	cspec spliceai
PP4	Not assessed	Not assessed: no tumor testing, germline-retention result, or somatic second-hit data were available.	cspec
PP5	N/A	Not applicable: PP5 is not applicable under the DICER1 VCEP, and the ClinVar record has no expert-panel submission.	cspec clinvar
BA1	Not met	Not met: the highest qualifying gnomAD v4.1 subpopulation frequency is 0.00261 in East Asians (76/29,110), below the >0.003 BA1 threshold.	cspec gnomad_v4 gnomad_v2
BS1	Met	Met (Strong): gnomAD v4.1 East Asian frequency 0.00261 (76/29,110 alleles) exceeds the >0.0003 BS1 threshold with adequate sample size.	cspec gnomad_v4
BS2	Met	Met (Supporting): gnomAD v4.1 reports 2 homozygotes overall, meeting the VCEP rule for homozygous observations lacking clinical information.	cspec gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no benign functional study, RNA evidence, or cleavage assay was available.	cspec
BS4	Not assessed	Not assessed: no phenotype-positive, genotype-negative relatives or segregation results were available.	cspec
BP1	N/A	Not applicable: the DICER1 VCEP designates BP1 as not applicable; truncating variants are only part of the disease spectrum.	cspec
BP2	Not assessed	Not assessed: no trans/cis observations with a pathogenic DICER1 variant, phase data, or parental testing were available.	cspec
BP3	N/A	Not applicable: the DICER1 VCEP explicitly marks BP3 as not applicable at this time.	cspec
BP4	Not assessed	Not assessed: although SpliceAI predicts no splice impact (max delta 0.012), the required MaxEntScan concordance result is unavailable.	cspec spliceai
BP5	N/A	Not applicable: the DICER1 VCEP marks BP5 as not applicable given the broad neoplasm spectrum; no alternate diagnosis is evaluated.	cspec
BP6	N/A	Not applicable: BP6 is not applicable under the DICER1 VCEP, and the ClinVar likely-benign submissions are non-expert.	cspec clinvar
BP7	Not assessed	Not assessed: BP7 requires BP4, which cannot be assessed without the required MaxEntScan result.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.