Variant classification summary

NM_177438.3:c.1510-4dupT

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

GRCh37: chr14:95583035 G>GA · GRCh38: chr14:95116698 G>GA

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

0.0014255479633815227 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Benign: BA1 is stand-alone because the African/African American gnomAD v4.1 allele frequency is 0.0131239.

2

Benign: BS1 is strong because the African/African American gnomAD v4.1 allele frequency is 0.0131239 with 935 variant alleles.

3

Benign: BS2 is supporting because gnomAD v4.1 reports six homozygous observations without clinical information.

Final determination: The DICER1 VCEP Version 1.4 point-based framework assigns Benign at a total score of -7 or below; BA1 (-8), BS1 (-4), and BS2 (-1) 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	N/A	Not applicable: c.1510-4dup is intronic at -4, outside the DICER1 VCEP PVS1 scope of nonsense/frameshift and canonical +/-1 or +/-2 splice variants.	cspec vcep_pvs1_decisiontree spliceai
PS1	Not assessed	Not assessed: no pathogenic DICER1 VCEP comparator at the same nucleotide or amino-acid change is documented for c.1510-4dupT.	cspec spliceai
PS2	Not assessed	Not assessed: no documented parental testing or confirmed de novo observation is available to calculate the DICER1 VCEP PS2 point total.	cspec
PS3	Not assessed	Not assessed: no variant-specific RNA or cleavage assay with validated controls and quantitative functional result is available for c.1510-4dupT.	cspec
PS4	Not assessed	Not assessed: no phenotype-point total or case-control enrichment result is available for NM_177438.3:c.1510-4dup.	cspec
PM1	N/A	Not applicable: c.1510-4dupT is intronic with protein consequence p.?, not a missense variant in an approved DICER1 critical domain.	cspec
PM2	Not met	Not met: gnomAD v4.1 overall AF 0.00142555 is far above the DICER1 VCEP PM2 threshold of <0.000005, with 2,181 observed alleles.	cspec gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: the DICER1 VCEP explicitly designates PM3 as not applicable for this autosomal-dominant disorder.	cspec
PM4	N/A	Not applicable: c.1510-4dup is intronic with protein consequence p.?, not an in-frame coding indel eligible for the DICER1 VCEP PM4 rule.	cspec
PM5	N/A	Not applicable: c.1510-4dupT is intronic with protein consequence p.?, so no same-residue missense comparison can be made.	cspec pm5_candidates
PM6	N/A	Not applicable: the DICER1 VCEP explicitly directs reviewers to use PS2 instead of PM6 for de novo evidence.	cspec
PP1	Not assessed	Not assessed: no affected relatives or documented segregation data are available to establish even the minimum 3–4 meioses required for PP1 Supporting.	cspec
PP2	N/A	Not applicable: the DICER1 VCEP marks PP2 not applicable, and c.1510-4dupT is intronic rather than missense.	cspec
PP3	Not assessed	Not assessed: SpliceAI max delta 0.016 is below PP3 thresholds, but the DICER1 rule requires concordant MaxEntScan, which is unavailable.	cspec spliceai
PP4	Not assessed	Not assessed: COSMIC reports 2 somatic occurrences, but no qualifying RNase IIIb second-hit and retention data are provided.	cspec
PP5	N/A	Not applicable: the DICER1 VCEP excludes PP5, and ClinVar has 0 expert-panel submissions for this exact variant.	cspec clinvar
BA1	Met	Met: gnomAD v4.1 African/African American AF 0.0131239 exceeds the DICER1 VCEP BA1 threshold of >0.003 with 935/71,244 alleles.	cspec gnomad_v4
BS1	Met	Met, strong: gnomAD v4.1 African/African American AF 0.0131239 exceeds the DICER1 VCEP BS1 threshold of >0.0003 with 935/71,244 alleles.	cspec gnomad_v4
BS2	Met	Met, supporting: gnomAD v4.1 reports 6 homozygotes, meeting the DICER1 VCEP requirement of at least 2 homozygous observations without clinical information.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific RNA or cleavage assay with replication, validated controls, and demonstrated normal function is available for c.1510-4dupT.	cspec
BS4	Not assessed	Not assessed: no phenotype-positive genotype-negative relatives or documented non-segregation observation is available for the DICER1 BS4 rule.	cspec
BP1	N/A	Not applicable: the DICER1 VCEP marks BP1 not applicable, and c.1510-4dupT is intronic rather than missense.	cspec
BP2	Not assessed	Not assessed: no affected-proband co-occurrence or phase evidence documents the VCEP threshold of one trans observation or three cis/unknown observations.	cspec
BP3	N/A	Not applicable: the DICER1 VCEP Version 1.4 explicitly designates BP3 as not applicable, regardless of this intronic duplication's repeat context.	cspec
BP4	Not assessed	Not assessed: SpliceAI max delta 0.016 is below the BP4 threshold, but the DICER1 rule requires concordant MaxEntScan, which is unavailable.	cspec spliceai
BP5	N/A	Not applicable: the DICER1 VCEP Version 1.4 explicitly excludes BP5 for this gene framework.	cspec
BP6	N/A	Not applicable: the DICER1 VCEP excludes BP6, and ClinVar has 0 expert-panel submissions for this exact variant.	cspec clinvar
BP7	N/A	Not applicable: c.1510-4dup is an intronic splice-region variant, not a synonymous coding variant, so BP7 is outside scope.	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.