Variant classification summary

NM_177438.3:c.3033G>A

DICER1 · NP_803187.1:p.(Ala1011=) · NM_177438.3

GRCh37: chr14:95572075 C>T · GRCh38: chr14:95105738 C>T

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.(Ala1011=)

gnomAD AF

0.006271010238561075 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The DICER1 NM_177438.3:c.3033G>A (NP_803187.1:p.(Ala1011=)) variant has been reported in ClinVar with multiple benign submissions.

2

This variant is common in population databases, including gnomAD v4.1 at 0.62710% overall and 11.88190% in the African/African American subpopulation (8910/74988 alleles, 594 homozygotes overall), which exceeds the DICER1 BA1 threshold of 0.3% and BS1 threshold of 0.03%.

3

SpliceAI predicts no significant splice impact, with a maximum delta score of 0.01, arguing against an abnormal splicing effect for this synonymous change, although BP4/BP7 were not fully applied because concordant MaxEntScan evidence was not identified.

Final determination: ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.4.0 v1.4.0 point-based framework yields a total score of -13, which maps to Benign under the specified Tavtigian-style ranges.

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	This synonymous variant does not create a premature stop, frameshift, or canonical ±1,2 splice-site change, and the reviewed PVS1 materials place it outside the DICER1 loss-of-function variant categories used for PVS1.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	Available evidence does not establish a DICER1 pathogenic comparator producing the same amino-acid outcome with equivalent splicing context, so PS1 was not assessed.	cspec spliceai
PS2	Not assessed	No confirmed de novo observation with parental testing was identified, so PS2 was not assessed.	cspec
PS3	Not assessed	No RNA study or other DICER1 functional assay demonstrating an abnormal effect for this variant was identified, so PS3 was not assessed.	cspec
PS4	Not assessed	No case-level phenotype-point evidence supporting enrichment in affected individuals was identified, so PS4 was not assessed.	cspec clinvar
PM1	N/A	This variant is synonymous and does not alter a residue in the DICER1 RNase IIIb missense hotspot framework used for PM1.	cspec hotspots
PM2	Not met	Population frequency is far above the DICER1 PM2 threshold of <0.000005. In gnomAD v4.1, this variant is present at 0.006271 overall and 0.118819 in the African/African American subpopulation; in gnomAD v2.1, it is present at 0.011682 overall and 0.121573 in the same subpopulation.	cspec gnomad_v4 gnomad_v2
PM3	N/A	The DICER1 specification lists PM3 as not applicable.	cspec
PM4	N/A	This variant is not an in-frame insertion or deletion, so PM4 is not applicable.	cspec
PM5	N/A	The reviewed PM5 candidate file indicates the DICER1 framework uses classic same-residue missense PM5 logic, and this variant is synonymous rather than missense-like.	cspec pm5_candidates
PM6	N/A	The DICER1 specification lists PM6 as not applicable.	cspec
PP1	Not assessed	No segregation data were identified, so PP1 was not assessed.	cspec
PP2	N/A	The DICER1 specification lists PP2 as not applicable.	cspec
PP3	Not met	Available computational evidence does not support a damaging or splice-altering effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and no other reviewed predictor provided evidence favoring pathogenicity for this synonymous change.	cspec spliceai
PP4	Not assessed	No tumor study showing retention of this germline variant with a qualifying DICER1 RNase IIIb hotspot second hit and no additional somatic DICER1 variants was identified, so PP4 was not assessed.	cspec hotspots
PP5	N/A	The DICER1 specification lists PP5 as not applicable.	cspec
BA1	Met	This variant exceeds the DICER1 BA1 threshold of >0.003 in a gnomAD subpopulation with >2,000 alleles tested and at least 5 variant alleles. In gnomAD v4.1, the African/African American subpopulation frequency is 0.118819 (8910/74988 alleles); gnomAD v2.1 similarly shows 0.121573 (3033/24948 alleles).	cspec gnomad_v4 gnomad_v2
BS1	Met	This variant exceeds the DICER1 BS1 threshold of >0.0003 in a gnomAD subpopulation with >2,000 alleles tested and at least 5 variant alleles. In gnomAD v4.1, the African/African American subpopulation frequency is 0.118819 (8910/74988 alleles), well above the threshold.	cspec gnomad_v4 gnomad_v2
BS2	Met	This variant is observed in many homozygous individuals in population databases lacking individual clinical information, meeting the DICER1 BS2 Supporting rule for 2 or more homozygous observations without clinical data. gnomAD v4.1 reports 594 homozygotes overall, and gnomAD v2.1 reports 195 homozygotes overall.	cspec gnomad_v4 gnomad_v2
BS3	Not assessed	No RNA assay showing normal splicing for this synonymous variant was identified, so BS3 was not assessed.	cspec spliceai
BS4	Not assessed	No non-segregation data in affected relatives were identified, so BS4 was not assessed.	cspec
BP1	N/A	The DICER1 specification lists BP1 as not applicable.	cspec
BP2	Not assessed	No evidence of this variant occurring in trans with a pathogenic or likely pathogenic DICER1 variant, or repeated cis/unknown-phase observations with different pathogenic variants, was identified.	cspec
BP3	N/A	The DICER1 specification lists BP3 as not applicable.	cspec
BP4	Not assessed	SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which argues against abnormal splicing, but the DICER1 BP4 rule for synonymous variants requires concordance of MaxEntScan and SpliceAI. Concordant MaxEntScan evidence was not identified.	cspec spliceai
BP5	N/A	The DICER1 specification lists BP5 as not applicable.	cspec
BP6	N/A	The DICER1 specification lists BP6 as not applicable.	cspec
BP7	Not assessed	This is a synonymous variant, but the DICER1 BP7 rule has a caveat that BP4 must also be met. Because concordant MaxEntScan and SpliceAI evidence needed for BP4 was not identified, BP7 was not assessed.	cspec spliceai

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