Variant classification summary

NM_177438.3:c.734+6C>T

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

GRCh37: chr14:95595803 G>A · GRCh38: chr14:95129466 G>A

Gene: DICER1 Transcript: NM_177438.3

Final call

VUS

Variant details

Gene

DICER1

Transcript

NM_177438.3

Protein

NP_803187.1:p.?

gnomAD AF

4.650684022606045e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Only PVS1, PM4, and BP3 were adjudicated. The DICER1 VCEP specification governs: PVS1 is not met for this noncanonical +6 intronic variant, while PM4 and BP3 are not applicable to its consequence type.

2

The governing DICER1 VCEP framework applies PS2, PP1, and BS4 but excludes PM6; the available evidence does not document parental testing, de novo status, informative segregation, or non-segregation.

3

No paper in the extracted literature set provides variant-specific de novo, segregation, or non-segregation evidence for NM_177438.3:c.734+6C>T.

4

The variant is an intronic c.734+6 substitution; PP3 and BP4 use the splice-impact path, while BP7 is out of scope because the variant is not synonymous.

5

The available SpliceAI max delta is 0.07, but the governing DICER1 PP3/BP4 rules require MaxEntScan and SpliceAI concordance, and MaxEntScan evidence is unavailable.

Final determination: Under the DICER1 VCEP Version 1.4 point-based framework, a total of -1 through 5 points corresponds to Uncertain Significance (Rule 3).

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: c.734+6C>T is outside the DICER1 VCEP +/-1/+/-2 splice rule and has SpliceAI maximum delta 0.07.	cspec spliceai pvs1_variant_assessment PMID:25741868
PS1	Not assessed	Not assessed: c.734+6C>T has SpliceAI max delta 0.07, but no qualifying same-nucleotide VCEP-pathogenic comparator with comparable splicing impact is available.	cspec spliceai
PS2	Not assessed	Not assessed: no documented de novo observation or confirmed parental testing is available to assign PS2 de novo points.	cspec
PS3	Not assessed	Not assessed: no variant-specific RNA or pre-miRNA cleavage assay is available; SpliceAI max delta 0.07 is predictive evidence, not functional validation.	cspec spliceai
PS4	Not assessed	Not assessed: the DICER1 VCEP requires ≥4 phenotype points for strong PS4, but no adjudicated phenotype-point total is available.	cspec
PM1	N/A	Not applicable: c.734+6C>T is intronic with protein consequence p.?, whereas DICER1 PM1 is restricted to putative missense variants in specified residues or domains.	cspec
PM2	Not met	Not met: gnomAD v4.1 total frequency was 4.65e-05, exceeding the DICER1 VCEP PM2 cutoff of <5e-06.	cspec gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: the DICER1 VCEP Version 1.4 specification explicitly excludes PM3 for this gene.	cspec
PM4	N/A	Not applicable: c.734+6C>T is an intronic single-nucleotide variant with no in-frame indel or protein-length change.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: c.734+6C>T is intronic with protein consequence p.?, not a missense variant eligible for same-residue PM5 comparison.	cspec pm5_candidates
PM6	N/A	Not applicable: the DICER1 VCEP explicitly excludes PM6 and directs all de novo evidence to PS2.	cspec
PP1	Not assessed	Not assessed: no affected relatives or countable segregating meioses are documented for this variant.	cspec
PP2	N/A	Not applicable: the DICER1 VCEP explicitly excludes PP2, and c.734+6C>T is intronic rather than missense.	cspec
PP3	Not assessed	Not assessed: SpliceAI max delta 0.07 is below the 0.2 PP3 threshold, but the DICER1 rule also requires unavailable MaxEntScan concordance.	cspec spliceai
PP4	Not assessed	Not assessed: PP4 requires a documented DICER1 RNase IIIb hotspot second hit with germline-variant retention, but no qualifying tumor result is available.	cspec
PP5	N/A	Not applicable: the DICER1 VCEP excludes PP5, and ClinVar shows 0 expert-panel submissions for this exact variant.	cspec clinvar
BA1	Not met	Not met: the highest gnomAD v4.1 subpopulation frequency was 5.68e-05, below the DICER1 VCEP BA1 threshold of >0.003.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Not met: the highest gnomAD v4.1 subpopulation frequency was 5.68e-05, below the DICER1 VCEP BS1 threshold of >0.0003.	cspec gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: gnomAD v4.1 reports 0 homozygotes, but no qualifying healthy homozygote or tumor-free female cohort is available for the VCEP BS2 rule.	cspec gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no repeated RNA assay or controlled cleavage assay demonstrates normal function; SpliceAI max delta 0.07 alone cannot establish BS3.	cspec spliceai
BS4	Not assessed	Not assessed: no phenotype-positive, genotype-negative relatives are documented to demonstrate non-segregation.	cspec
BP1	N/A	Not applicable: the DICER1 VCEP explicitly excludes BP1, and c.734+6C>T is intronic rather than missense.	cspec
BP2	Not assessed	Not assessed: no qualifying trans observation or three cis/phase-unknown observations with two or more P/LP DICER1 variants are documented.	cspec
BP3	N/A	Not applicable: the DICER1 VCEP excludes BP3, and this variant is an intronic substitution rather than an in-frame deletion.	cspec pvs1_variant_assessment
BP4	Not assessed	Not assessed: SpliceAI max delta 0.07 meets the <=0.1 BP4 threshold, but the DICER1 rule also requires unavailable MaxEntScan concordance.	cspec spliceai
BP5	N/A	Not applicable: the DICER1 VCEP explicitly excludes BP5 because alternate-molecular-basis evidence is insufficient for this disorder.	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.734+6C>T is intronic, whereas BP7 applies only to synonymous variants.

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