Variant classification summary

NM_177438.3:c.4206+9del

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

GRCh37: chr14:95566107 AC>A · GRCh38: chr14:95099770 AC>A

Gene: DICER1 Transcript: NM_177438.3

Final call

Benign

BA1 stand-alone benign BS1 strong BS2 supporting

Variant details

Gene

DICER1

Transcript

NM_177438.3

Protein

NP_803187.1:p.?

gnomAD AF

0.3521707478040782 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BA1 (stand-alone benign): allele frequency above 0.003 in multiple gnomAD v4.1 subpopulations, most strikingly East Asian 0.485669.

2

BS1 (strong): allele frequency above 0.0003 in multiple gnomAD v4.1 subpopulations meeting size and allele-count requirements.

3

BS2 (supporting): thousands of homozygous carriers in gnomAD v4.1.

4

Overall Benign: BA1 (-8) plus BS1 strong (-4) and BS2 supporting (-1) total -13 points, which maps to Benign.

Final determination: Under the DICER1 VCEP v1.4 Tavtigian point-based framework, a total evidence score of -13 is at or below the Benign threshold of -7.

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 non-canonical intronic deletion is outside the PVS1 splice-variant entry conditions, and SpliceAI max delta 0.004 predicts no splice impact.	cspec spliceai vcep_pvs1_decisiontree
PS1	N/A	Not applicable: PS1 requires a same-amino-acid or same-nucleotide comparison, which this intronic deletion with protein consequence p.? cannot support.	cspec
PS2	Not assessed	Not assessed: no proband-level de novo observation with parental genotypes and confirmed maternity and paternity was documented.	cspec
PS3	Not assessed	Not assessed: no variant-specific RNA splicing assay or in vitro DICER1 cleavage assay data were available.	cspec PMID:25741868
PS4	Not assessed	Not assessed: no phenotype-pointed probands, case-control comparison, or exact-variant case series were available from which to assign points.	cspec gnomad_v4
PM1	N/A	Not applicable: PM1 targets missense variants affecting DICER1 metal-ion-binding or RNase IIIb-domain residues; this is an intronic deletion (p.?).	cspec
PM2	Not met	Not met: the variant is common in gnomAD v4.1 (overall allele frequency 0.352171), incompatible with PM2 rarity.	cspec gnomad_v4
PM3	N/A	Not applicable: the DICER1 VCEP excludes PM3 because DICER1-related tumor predisposition is autosomal dominant.	cspec
PM4	Not met	Not met: this intronic deletion with protein consequence p.? is not an in-frame protein indel or stop-loss variant as PM4 requires.	cspec spliceai
PM5	N/A	Not applicable: PM5 compares missense changes at the same residue; this intronic deletion has no defined amino-acid residue.	cspec
PM6	N/A	Not applicable: the DICER1 VCEP directs all de novo evidence to PS2 instead of PM6.	cspec
PP1	Not assessed	Not assessed: no affected relatives with documented co-segregating genotypes or countable meioses were available.	cspec
PP2	N/A	Not applicable: the DICER1 VCEP designates PP2 as not applicable, and the variant is intronic rather than missense.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.004 predicts no splicing impact, and no MaxEntScan result is available to show the required concordance.	cspec spliceai
PP4	Not assessed	Not assessed: no tumor sequencing showed the germline variant retained with a somatic RNase IIIb hotspot second hit.	cspec
PP5	N/A	Not applicable: the DICER1 VCEP excludes PP5, and the ClinVar record has no expert-panel submissions.	cspec clinvar
BA1	Met	Met (stand-alone benign): gnomAD v4.1 allele frequency exceeds the 0.003 threshold in multiple subpopulations, including East Asian 0.485669 (5524/11374 alleles).	cspec gnomad_v4
BS1	Met	Met (strong): gnomAD v4.1 allele frequency exceeds the 0.0003 threshold in multiple subpopulations meeting sample-size and allele-count requirements.	cspec gnomad_v4
BS2	Met	Met (supporting): gnomAD v4.1 contains thousands of homozygous observations, far exceeding the required two.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no repeated variant-specific RNA or cleavage assay data demonstrating absence of splicing impact were available.	cspec PMID:25741868
BS4	Not assessed	Not assessed: no genotype-negative affected relatives or familial genotype results were documented.	cspec
BP1	N/A	Not applicable: the DICER1 VCEP designates BP1 as not applicable, and the variant is intronic rather than missense.	cspec
BP2	Not assessed	Not assessed: no observations in trans or cis with pathogenic DICER1 variants, or other allelic data, were documented.	cspec
BP3	N/A	Not applicable: BP3 is excluded by the DICER1 VCEP specification.	cspec
BP4	Not assessed	Not assessed: BP4 requires concordant MaxEntScan and SpliceAI predictions of no splicing effect; SpliceAI max delta is 0.004, but no MaxEntScan result is available.	cspec spliceai
BP5	N/A	Not applicable: BP5 is excluded by the DICER1 VCEP specification.	cspec
BP6	N/A	Not applicable: the DICER1 VCEP excludes BP6, and the ClinVar record has no expert-panel submissions.	cspec clinvar
BP7	Not assessed	Not assessed: position +9 meets the BP7 positional requirement, but BP4 must be applied first and cannot be assessed without MaxEntScan.	cspec spliceai

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