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): gnomAD v4.1 allele frequency 35.2% overall and 48.6% in East Asians far exceeds the >0.3% BA1 threshold.

2

BS1 (strong): the same gnomAD frequency far exceeds the >0.03% BS1 threshold, incompatible with a rare tumor-predisposition allele.

3

BS2 (supporting): 7,262 homozygous carriers in gnomAD far exceed the two-observation BS2 threshold.

4

Combined, BA1 (-8) + BS1 (-4) + BS2 (-1) = -13 points, classifying this variant as Benign under the DICER1 VCEP framework.

Final determination: Under the DICER1 VCEP Tavtigian point framework, a total score of -7 or lower is classified as Benign; the applied criteria total -13.

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: intronic +9 deletion is outside canonical splice sites, with no RNA evidence of aberrant splicing or truncation.	cspec vcep_pvs1_decisiontree
PS1	Not assessed	Not assessed: no pathogenic ClinGen DICER1 comparator at the same nucleotide was available to establish an equal-or-worse splice impact.	cspec
PS2	Not assessed	Not assessed: no documented de novo occurrence with parental testing or confirmed maternity and paternity was available.	cspec
PS3	Not assessed	Not assessed: no variant-specific RNA or cleavage assay was available; computational SpliceAI alone cannot meet PS3.	cspec
PS4	Not met	Not met: gnomAD allele frequency 35.2% makes a pathogenic population effect implausible, and PS4 is excluded when BA1/BS1 are met.	cspec gnomad_v4
PM1	N/A	Not applicable: PM1 applies only to missense variants; this intronic deletion has no protein residue to evaluate.	cspec
PM2	Not met	Not met: gnomAD allele frequency 35.2% vastly exceeds the <0.0005% PM2 rarity threshold.	cspec gnomad_v4
PM3	N/A	Not applicable: DICER1 is autosomal dominant, so the recessive allelic-phase criterion PM3 does not apply.	cspec
PM4	Not met	Not met: no in-frame protein change or stop-loss is demonstrated for this intronic deletion.	cspec
PM5	N/A	Not applicable: PM5 requires a same-residue missense comparator; this variant is intronic, not missense.	cspec pm5_candidates
PM6	N/A	Not applicable: the DICER1 VCEP directs de novo evidence to PS2 instead of PM6.	cspec
PP1	Not assessed	Not assessed: no variant-carrying affected relatives or informative meioses were documented.	cspec
PP2	N/A	Not applicable: PP2 is excluded by the DICER1 VCEP; the variant is also intronic rather than missense.	cspec
PP3	Not assessed	Not assessed: MaxEntScan data were unavailable, so the required SpliceAI/MaxEntScan concordance could not be established.	cspec spliceai
PP4	Not assessed	Not assessed: no paired tumor findings (somatic RNase IIIb hotspot second hit) were available for the PP4 tumor rule.	cspec
PP5	N/A	Not applicable: the DICER1 VCEP does not use PP5, and the ClinVar record has no expert-panel submission.	cspec clinvar
BA1	Met	Met (stand-alone benign): gnomAD v4.1 allele frequency 35.2% overall and 48.6% in East Asians far exceeds the >0.3% BA1 threshold.	cspec gnomad_v4
BS1	Met	Met (strong): gnomAD allele frequency 35.2% far exceeds the >0.03% BS1 threshold, incompatible with a rare disease-causing allele.	cspec gnomad_v4
BS2	Met	Met (supporting): 7,262 homozygous carriers in gnomAD far exceed the two-observation BS2 threshold.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no benign functional assay (RNA or cleavage) was available for this variant.	cspec
BS4	Not assessed	Not assessed: no family genotypes or documented non-segregation were available.	cspec
BP1	N/A	Not applicable: BP1 is excluded by the DICER1 VCEP; the variant is intronic, not missense.	cspec
BP2	Not assessed	Not assessed: no family, phase, or co-occurring pathogenic DICER1 variant observations were available.	cspec
BP3	N/A	Not applicable: BP3 is excluded by the DICER1 VCEP and does not apply to intronic deletions.	cspec
BP4	Not assessed	Not assessed: MaxEntScan data were unavailable, so the required SpliceAI/MaxEntScan concordance could not be established.	cspec spliceai
BP5	N/A	Not applicable: BP5 is excluded by the DICER1 VCEP because of the broad DICER1 neoplasm spectrum.	cspec
BP6	N/A	Not applicable: the DICER1 VCEP does not use BP6, and the ClinVar record has no expert-panel submission.	cspec clinvar
BP7	Not assessed	Not assessed: BP7 requires BP4 to be met, but BP4 could not be assessed without MaxEntScan data.	cspec spliceai

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