Variant classification summary

NM_177438.3:c.4014G>A

DICER1 · NP_803187.1:p.(Ala1338=) · NM_177438.3

GRCh37: chr14:95569719 C>T · GRCh38: chr14:95103382 C>T

Gene: DICER1 Transcript: NM_177438.3

Final call

Benign

BA1 stand-alone benign BS1 strong BS2 supporting BP4 supporting BP7 supporting

Variant details

Gene

DICER1

Transcript

NM_177438.3

Protein

NP_803187.1:p.(Ala1338=)

gnomAD AF

0.0012631800666592326 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BA1 (stand-alone benign): Finnish gnomAD v4.1 allele frequency 0.423% (271/64,026) exceeds the 0.3% subpopulation threshold.

2

BS1 (strong): same Finnish allele frequency 0.423% exceeds the 0.03% subpopulation threshold.

3

BS2 (supporting): 6 homozygotes in gnomAD v4.1 meet the 2+ homozygosity observation threshold.

4

BP4 (supporting): SpliceAI predicts no splice effect (max delta 0.004).

5

BP7 (supporting): silent variant p.(Ala1338=) meets the VCEP BP7 rule.

6

Benign: combined -15 points under the DICER1 VCEP v1.4 point framework falls in the Rule5 range (<=-7).

Final determination: ClinGen DICER1 VCEP v1.4 point-based framework: total score -15 falls within Rule5 (<=-7), yielding Benign; BA1 stand-alone benign is independently sufficient.

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	Not applicable: a synonymous substitution creates no null allele, and SpliceAI predicts no splice effect (max delta 0.00).	cspec pvs1_variant_assessment pvs1_gene_context spliceai
PS1	N/A	Not applicable: the variant is synonymous (p.(Ala1338=)), so there is no amino acid change to compare against a pathogenic missense.	cspec
PS2	Not assessed	Not assessed: no parental testing, maternity/paternity confirmation, or de novo observations were available for this variant.	cspec
PS3	Not assessed	Not assessed: no RNA splicing or in vitro microRNA-cleavage assay data on this variant were available.
PS4	Not met	Not met: Finnish gnomAD v4.1 allele frequency 0.423% (271/64,026) exceeds the VCEP BA1 threshold of 0.3%, excluding PS4.	cspec gnomad_v4
PM1	N/A	Not applicable: PM1 is limited to missense variants at metal-binding or RNase IIIb hotspot codons; this variant is synonymous at residue 1338.	cspec
PM2	Not met	Not met: gnomAD v4.1 overall allele frequency 0.126% (2,039 alleles, 6 homozygotes) far exceeds the PM2 threshold of <0.0005%.	cspec gnomad_v4 gnomad_v2 gnomad_canada
PM3	N/A	Not applicable: the DICER1 VCEP specification designates PM3 as not applicable for this gene.	cspec
PM4	N/A	Not applicable: PM4 requires an in-frame indel, and this single-nucleotide synonymous substitution changes no protein length.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: PM5 compares missense changes at the same residue; this synonymous variant creates no amino acid substitution.	cspec pm5_candidates
PM6	N/A	Not applicable: the DICER1 VCEP directs de novo evidence to PS2, so PM6 is unused.	cspec
PP1	Not assessed	Not assessed: no affected relatives, genotype results, or meiosis counts were available to assess segregation.	cspec
PP2	N/A	Not applicable: the DICER1 VCEP defines no PP2 missense-constraint rule for this gene.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.004 is far below any splice-disruption threshold; REVEL does not apply to this synonymous variant.	spliceai cspec
PP4	Not assessed	Not assessed: no tumor-testing result demonstrating a somatic DICER1 hotspot second hit was supplied.	cspec
PP5	Not met	Not met: ClinVar variation 221087 has no expert-panel assertion, only ordinary clinical-laboratory submissions.	clinvar
BA1	Met	Met (stand-alone benign): Finnish gnomAD v4.1 allele frequency 0.423% (271/64,026) exceeds the 0.3% BA1 threshold with sufficient allele counts.	cspec gnomad_v4
BS1	Met	Met (strong): Finnish gnomAD v4.1 allele frequency 0.423% (271/64,026) exceeds the 0.03% BS1 threshold.	cspec gnomad_v4
BS2	Met	Met (supporting): gnomAD v4.1 reports 6 homozygotes, meeting the threshold of 2+ homozygosity observations without clinical information.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no RNA or in vitro cleavage assay data on this variant were available; in silico predictions do not qualify for BS3.
BS4	Not assessed	Not assessed: no pedigree or genotype-negative relatives were available to assess lack of segregation.	cspec
BP1	N/A	Not applicable: the DICER1 VCEP defines no BP1 rule for this gene.	cspec
BP2	Not assessed	Not assessed: no second pathogenic DICER1 variant or cis/trans phase observation was available.	cspec
BP3	N/A	Not applicable: the DICER1 VCEP marks BP3 unused, and this variant is not an in-frame indel.	cspec
BP4	Met	Met (supporting): SpliceAI predicts no splice effect (max delta 0.004). Flagged for human review: MaxEntScan concordance is not yet confirmed.	spliceai cspec
BP5	N/A	Not applicable: the DICER1 VCEP prohibits BP5 given the broad DICER1-related neoplasm spectrum.	cspec
BP6	Not met	Not met: ClinVar Benign/Likely benign assertions are from ordinary laboratories with no expert-panel assertion.	clinvar
BP7	Met	Met (supporting): silent variant p.(Ala1338=) qualifies under the VCEP BP7 rule, contingent on BP4.	spliceai cspec

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.