LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_177438.3:c.735-23A>G
DICER1
· NP_803187.1:p.?
· NM_177438.3
GRCh37: chr14:95593108 T>C
·
GRCh38: chr14:95126771 T>C
Gene:
DICER1
Transcript:
NM_177438.3
Final call
Likely Benign
BP4 supporting
BP7 supporting
Variant details
Gene
DICER1
Transcript
NM_177438.3
Protein
NP_803187.1:p.?
gnomAD AF
1.3798595697203617e-05 (v4.1)
ClinVar
Likely benign
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BP4 (Supporting): SpliceAI predicts no splicing effect for this intronic variant (max delta 0.001).
2
BP7 (Supporting): intronic position -23 is beyond -21 from the acceptor site, and BP4 is met as required.
3
Synthesis: a total Tavtigian score of -2 from the two supporting benign criteria classifies this variant as Likely Benign under the DICER1 VCEP v1.4 framework.
Final determination:
Total score -2 falls in Rule4 range (>=-6 and >=-2), yielding Likely Benign per DICER1 VCEP v1.4.
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: this deep intronic variant is outside the canonical +/-1,2 splice sites and is not a nonsense/frameshift change, so no loss-of-function mechanism applies. |
cspec
spliceai
pvs1_variant_assessment
|
| PS1 | N/A | Not applicable: the variant has no predicted protein consequence and no VCEP-classified pathogenic variant exists at this nucleotide to compare. |
cspec
|
| PS2 | Not assessed | Not assessed: no de novo observation, parental genotypes, or confirmation data for this variant were available. |
cspec
|
| PS3 | Not assessed | Not assessed: no RNA splicing or microRNA cleavage assay data for this variant were available. |
|
| PS4 | Not assessed | Not assessed: no case series, unrelated-proband phenotype observations, or case-control counts were available. |
cspec
|
| PM1 | N/A | Not applicable: PM1 is restricted to missense variants at RNase IIIb hotspot codons, and this intronic variant changes no residue. |
cspec
|
| PM2 | Not met | Not met: gnomAD v4.1 frequency 1.38e-05 (21/1,521,894 alleles, 19 in European non-Finnish) exceeds the <0.000005 PM2 threshold. |
cspec
gnomad_v4
|
| PM3 | N/A | Not applicable: the DICER1 VCEP designates PM3 as not applicable for this autosomal dominant disorder. |
cspec
|
| PM4 | N/A | Not applicable: PM4 applies only to in-frame indels, and this is a single-nucleotide substitution with no predicted protein change. |
cspec
spliceai
|
| PM5 | N/A | Not applicable: PM5 applies to missense variants at the same codon, and this intronic variant has no amino acid change. |
cspec
|
| PM6 | N/A | Not applicable: the DICER1 VCEP directs de novo evidence to PS2 rather than PM6. |
cspec
|
| PP1 | Not assessed | Not assessed: no affected relatives, family structure, or meiosis-count data were available. |
cspec
|
| PP2 | N/A | Not applicable: the DICER1 VCEP designates PP2 as not applicable, and the variant is intronic with no protein consequence. |
cspec
|
| PP3 | Not met | Not met: SpliceAI predicts no splicing effect (max delta 0.001), and the intronic variant falls outside the missense REVEL/BayesDel sub-path. |
cspec
spliceai
|
| PP4 | Not assessed | Not assessed: no tumor-testing or proband phenotype results for this variant were available. |
cspec
|
| PP5 | N/A | Not applicable: the DICER1 VCEP designates PP5 as not applicable, and the ClinVar record lacks an expert-panel submission. |
cspec
clinvar
|
| BA1 | Not met | Not met: highest gnomAD v4.1 subpopulation frequency 1.74e-05 (1/57,450) is far below the >0.003 BA1 threshold. |
cspec
gnomad_v4
|
| BS1 | Not met | Not met: highest gnomAD v4.1 subpopulation frequency 1.74e-05 (1/57,450) is below the >0.0003 BS1 threshold. |
cspec
gnomad_v4
|
| BS2 | Not met | Not met: gnomAD v4.1 reports zero homozygotes, and no healthy-individual or parental-testing observations were available. |
cspec
gnomad_v4
|
| BS3 | Not assessed | Not assessed: no RNA or cleavage assay data demonstrating absence of splicing impact were available. |
|
| BS4 | Not assessed | Not assessed: no genotype or phenotype data for first- to third-degree relatives were available. |
cspec
|
| BP1 | N/A | Not applicable: the DICER1 VCEP designates BP1 as not applicable for this gene specification. |
cspec
|
| BP2 | Not assessed | Not assessed: no phase, parental, or second-variant data existed to evaluate the in trans/in cis threshold. |
cspec
|
| BP3 | N/A | Not applicable: the DICER1 VCEP designates BP3 as not applicable for this gene. |
cspec
|
| BP4 | Met | Met (Supporting): SpliceAI predicts no splicing effect (max delta 0.001), satisfying the BP4 concordance rule for intronic variants. |
cspec
spliceai
|
| BP5 | N/A | Not applicable: the DICER1 VCEP designates BP5 as not applicable due to the broad neoplasm spectrum. |
cspec
|
| BP6 | N/A | Not applicable: the DICER1 VCEP designates BP6 as not applicable, and the ClinVar record lacks an expert-panel assertion. |
cspec
clinvar
|
| BP7 | Met | Met (Supporting): intronic position -23 lies beyond -21 from the acceptor site, with no splicing impact predicted. |
cspec
spliceai
|
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.