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Variant interpretation report

DICER1 c.4680G>A, p.(Ala1560=)

NM_177438.3:c.4680G>A NP_803187.1:p.(Ala1560=) View identifiers
Classification
Benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.

Benign.A benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About DICER1

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen DICER1 VCEP v1.4.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 3
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone

Population frequency exceeds the DICER1 BA1 threshold of >0.003 in a qualifying gnomAD subpopulation. In gnomAD v4.1, the African/African American subpopulation frequency is 0.11919 (8940/75006 alleles), which is far above the 0.003 threshold and includes far more than 5 alleles with >2000 alleles tested.

BS1Strong
BS1 · strong

Population frequency exceeds the DICER1 BS1 threshold of >0.0003 in a qualifying gnomAD subpopulation. In gnomAD v4.1, the African/African American subpopulation frequency is 0.11919 (8940/75006 alleles), which is far above the 0.0003 threshold.

BS2Supporting
BS2 · supporting

This variant is observed in homozygous state in population datasets lacking detailed clinical information, which supports BS2 at the supporting level under the DICER1 specification. gnomAD v4.1 reports 596 homozygotes, gnomAD v2.1 reports 195 homozygotes, and gnomAD-Canada reports 11 homozygotes.

Recorded classification: Benign

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: BA1 stand-alone benign (-8) + BS1 strong (-4) + BS2 supporting (-1) = -13 points, which maps to Benign.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
10,186 / 1,614,164 alleles

gnomAD v4.1: 10,186 / 1,614,164 alleles. Recorded AF 0.00631039. Recorded homozygote count 596.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.0117076; MAF= 1.17076%, 3311/282808 alleles, homozygotes = 195) and has highest observed frequency in the African/African American population (AF= 0.122266; MAF= 12.22658%, 3052/24962 alleles, homozygotes = 193); grpmax FAF= 0.1183.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00863286; MAF= 0.86329%, 159/18418 alleles, homozygotes = 11) and has highest observed frequency in the afr population (AF= 0.140196; grpmax FAF95= 0.121485).

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
12 reported laboratory submissions

11 Benign · 1 benign.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

For specialists

Technical detail

ACMG/AMP criteria under ClinGen DICER1 VCEP v1.4.0, with the data and sources behind each one.

28 criteria with recorded statuses: 3 met · 3 not met · 10 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Met Not met Not assessed Not applicable

The DICER1 c.4680G>A (p.Ala1560=) variant has been reported in ClinVar with benign classifications from multiple clinical laboratories.

This variant is common in population databases, including gnomAD v4.1 with total allele frequency 0.00631 and African/African American allele frequency 0.11919, which is well above the DICER1 BA1 threshold of 0.003; gnomAD-Canada also shows allele frequency 0.00863 with 11 homozygotes.

Computational data do not support a splice-disrupting effect, with SpliceAI max delta score 0.01, and the REVEL score is 0.07.

Met · 3

BA1 Stand alonePopulation frequency exceeds the DICER1 BA1 threshold of >0.003 in a qualifying gnomAD subpopulation. In gnomAD v4.1, the African/African American subpopulation frequency is 0.11919 (8940/75006 alleles), which is far above the 0.003 threshold and includes far more than 5 alleles with >2000 alleles tested. Details ▾Hide ▴
Rule
BA1 Stand Alone: frequency >0.003 in a qualifying gnomAD subpopulation.
Evidence considered
  • gnomAD v4.1 African/African American AF 0.11919046476281897 (8940/75006)
Sources
BS1 StrongPopulation frequency exceeds the DICER1 BS1 threshold of >0.0003 in a qualifying gnomAD subpopulation. In gnomAD v4.1, the African/African American subpopulation frequency is 0.11919 (8940/75006 alleles), which is far above the 0.0003 threshold. Details ▾Hide ▴
Rule
BS1 Strong: frequency >0.0003 in a qualifying gnomAD subpopulation.
Evidence considered
  • gnomAD v4.1 African/African American AF 0.11919046476281897 (8940/75006)
Sources
BS2 SupportingThis variant is observed in homozygous state in population datasets lacking detailed clinical information, which supports BS2 at the supporting level under the DICER1 specification. gnomAD v4.1 reports 596 homozygotes, gnomAD v2.1 reports 195 homozygotes, and gnomAD-Canada reports 11 homozygotes. Details ▾Hide ▴
Rule
BS2 Supporting: 2+ observations of homozygosity in individuals lacking clinical information.
Evidence considered
  • gnomAD v4.1 homozygotes 596
  • gnomAD v2.1 homozygotes 195
  • gnomAD-Canada homozygotes 11
Sources

Not met · 3 · evaluated, threshold not reached

PS1 No pathogenic same-amino-acid comparator identified for this synonymous change, so PS1 is not supported. Details ▾Hide ▴
Rule
Requires a pathogenic comparator with the same amino acid change and no worse splicing impact.
Evidence considered
  • No pathogenic same-amino-acid comparator identified
Sources
PM2 Population frequency is far above the DICER1 PM2 threshold of <0.000005. In gnomAD v4.1, the total allele frequency is 0.00631 and the African/African American subpopulation frequency is 0.11919 (8940/75006 alleles). Details ▾Hide ▴
Rule
Requires allele frequency <0.000005 with no more than one allele in any subpopulation.
Evidence considered
  • gnomAD v4.1 total AF 0.006310387296458104
  • gnomAD v4.1 African/African American AF 0.11919046476281897 (8940/75006)
Sources
PP3 Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a max delta score of 0.01, and the REVEL score is 0.07, well below the DICER1 PP3 missense threshold of >=0.750. Details ▾Hide ▴
Rule
Requires qualifying damaging computational evidence under the DICER1 specification.
Evidence considered
  • SpliceAI max delta 0.01
  • REVEL 0.07
Still missing
  • If desired
  • additional splice predictor concordance such as MaxEntScan
Sources

Not assessed · 10 · no assessment recorded

PS2 No confirmed de novo data were identified for this variant, so PS2 cannot be assessed. Details ▾Hide ▴
Rule
Requires de novo points under the DICER1 specification.
Evidence considered
  • No de novo observations identified
Still missing
  • Confirmed parental testing or de novo evidence
Sources
PS3 No RNA assay or other DICER1-validated functional assay was identified showing an abnormal effect for this variant, so PS3 is not met. Details ▾Hide ▴
Rule
Requires RNA or validated functional assay evidence showing a damaging effect.
Evidence considered
  • No variant-specific functional assay identified
  • SpliceAI alone is not a functional assay
Still missing
  • Variant-specific RNA or functional assay evidence
Sources
PS4 No case-level phenotype point data were identified to show enrichment in individuals with DICER1-related disease, so PS4 cannot be applied. Details ▾Hide ▴
Rule
Requires phenotype points under the DICER1 specification.
Evidence considered
  • No phenotype-point evidence identified
  • ClinVar contains benign submissions rather than case-enrichment data
Still missing
  • Phenotype-point case data under the DICER1 specification
Sources
PP1 No segregation data were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
Requires informative segregation across meioses under the DICER1 specification.
Evidence considered
  • No segregation evidence identified
Still missing
  • Family segregation data with informative meioses
Sources
PP4 No tumor testing evidence was identified showing a qualifying DICER1 hotspot second hit with retention of this germline variant, so PP4 cannot be applied. Details ▾Hide ▴
Rule
Requires qualifying tumor second-hit evidence under the DICER1 specification.
Evidence considered
  • No qualifying tumor second-hit evidence identified
  • Cancer Hotspots did not show this variant as a hotspot
Still missing
  • Tumor sequencing demonstrating a qualifying somatic hotspot second hit and retention of the germline allele
Sources
BS3 No RNA study was identified showing no splicing impact for this synonymous variant, so BS3 cannot be applied. Details ▾Hide ▴
Rule
Requires RNA or qualifying benign functional evidence under the DICER1 specification.
Evidence considered
  • No RNA assay identified
  • SpliceAI is predictive rather than functional evidence
Still missing
  • Variant-specific RNA assay showing no splicing impact
  • ideally observed more than once
Sources
BS4 No segregation data were identified showing the variant absent in phenotype-positive relatives, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
Requires genotype-negative phenotype-positive relatives under the DICER1 specification.
Evidence considered
  • No negative segregation evidence identified
Still missing
  • Segregation data in phenotype-positive relatives
Sources
BP2 No co-occurrence or phase data were identified to support BP2. Details ▾Hide ▴
Rule
Requires qualifying trans or repeated cis/unknown-phase observations under the DICER1 specification.
Evidence considered
  • No co-occurrence or phase evidence identified
Still missing
  • Documented in trans observation with a pathogenic/likely pathogenic DICER1 variant or repeated cis/unknown-phase observations as specified
Sources
BP4 Available computational evidence argues against a splice-disrupting effect, with SpliceAI max delta score 0.01 and REVEL 0.07, but the DICER1 specification for synonymous/non-coding BP4 calls for concordance of MaxEntScan and SpliceAI. MaxEntScan output was not identified, so BP4 was not fully established. Details ▾Hide ▴
Rule
For synonymous variants, BP4 requires concordance of MaxEntScan and SpliceAI showing no splicing effect.
Evidence considered
  • SpliceAI max delta 0.01
  • REVEL 0.07
  • No MaxEntScan output identified
Still missing
  • MaxEntScan result to confirm required predictor concordance for synonymous BP4
Sources
BP7 This is a synonymous variant, but the DICER1 BP7 rule requires BP4 and also no evidence that the nucleotide is highly conserved. BP4 was not fully established because the required MaxEntScan result was not identified, and no conservation assessment was identified. Details ▾Hide ▴
Rule
BP7 applies to silent variants only if BP4 is met and conservation does not argue against benignity.
Evidence considered
  • Synonymous consequence p.(Ala1560=)
  • SpliceAI max delta 0.01
  • No MaxEntScan or conservation assessment identified
Still missing
  • MaxEntScan result for BP4 prerequisite
  • Conservation assessment for the altered nucleotide
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis synonymous variant does not fall into the DICER1 loss-of-function categories used for PVS1, and the variant-level PVS1 review did not identify a nonsense, frameshift, or canonical +/-1,2 splice mechanism. Details ▾Hide ▴
Rule
DICER1 PVS1 applies to loss-of-function variant classes, not to this synonymous substitution.
Evidence considered
  • Synonymous consequence p.(Ala1560=)
  • Generic PVS1 scaffold marked variant outside null-variant buckets
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessment
PM1 N/AThis variant is synonymous and is not a missense change at a DICER1 RNase IIIb hotspot residue or elsewhere in the RNase IIIb missense domain used for PM1. Details ▾Hide ▴
Rule
Applies to specified missense residues in the RNase IIIb domain.
Evidence considered
  • Synonymous consequence p.(Ala1560=)
Sources
PM3 VCEPPM3 is marked not applicable in the DICER1 specification. Details ▾Hide ▴
VCEP rule
Not applicable in the DICER1 specification.
Evidence considered
  • DICER1 specification marks PM3 not applicable
Sources
PM4 N/AThis variant is not an in-frame insertion or deletion, so PM4 does not apply. Details ▾Hide ▴
Rule
Applies to in-frame indels under the DICER1 specification.
Evidence considered
  • Synonymous SNV
Sources
PM5 N/AThe DICER1 PM5 rule is classic same-residue missense logic, and this variant is not missense-like, so PM5 is not applicable. Details ▾Hide ▴
Rule
Applies to qualifying same-residue missense comparisons only.
Evidence considered
  • PM5 candidate review marked variant not eligible for classic same-residue missense PM5
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is marked not applicable in the DICER1 specification. Details ▾Hide ▴
VCEP rule
Not applicable in the DICER1 specification.
Evidence considered
  • DICER1 specification marks PM6 not applicable
Sources
PP2 VCEPPP2 is marked not applicable in the DICER1 specification. Details ▾Hide ▴
VCEP rule
Not applicable in the DICER1 specification.
Evidence considered
  • DICER1 specification marks PP2 not applicable
Sources
PP5 VCEPPP5 is marked not applicable in the DICER1 specification. Details ▾Hide ▴
VCEP rule
Not applicable in the DICER1 specification.
Evidence considered
  • DICER1 specification marks PP5 not applicable
Sources
BP1 VCEPBP1 is marked not applicable in the DICER1 specification. Details ▾Hide ▴
VCEP rule
Not applicable in the DICER1 specification.
Evidence considered
  • DICER1 specification marks BP1 not applicable
Sources
BP3 VCEPBP3 is marked not applicable in the DICER1 specification. Details ▾Hide ▴
VCEP rule
Not applicable in the DICER1 specification.
Evidence considered
  • DICER1 specification marks BP3 not applicable
Sources
BP5 VCEPBP5 is marked not applicable in the DICER1 specification. Details ▾Hide ▴
VCEP rule
Not applicable in the DICER1 specification.
Evidence considered
  • DICER1 specification marks BP5 not applicable
Sources
BP6 VCEPBP6 is marked not applicable in the DICER1 specification. Details ▾Hide ▴
VCEP rule
Not applicable in the DICER1 specification.
Evidence considered
  • DICER1 specification marks BP6 not applicable
Sources

Identifiers

Gene
DICER1
Transcript
NM_177438.3
Coding (HGVS c.)
NM_177438.3:c.4680G>A
Protein (HGVS p.)
NP_803187.1:p.(Ala1560=)
GRCh38
chr14:95096240 C>T
GRCh37
chr14:95562577 C>T
ClinVar
261925

Gene diagram

Every interpreted variant in DICER1, mapped onto the exon structure of NM_177438.3. Select a row to find it on the plot.

DICER1NM_177438.3
Fetching transcript structure from UCSC…
gnomAD v4.1 10,186 / 1,614,164 alleles AF 0.00631 · 596 homozygotes · FAF 0.117
gnomAD v2.1 3,311 / 282,808 alleles AF 0.0117 · 195 homozygotes · FAF 0.118
gnomAD-Canada v1.0 159 / 18,418 alleles AF 0.00863 · 11 homozygotes · FAF 0.121

By genetic ancestry

gnomAD v4.1

AF 0.0063 · 10186 / 1,614,164 alleles · 596 hom · FAF 0.12
African/African American8940 / 75,006 0.12577 hom
Remaining individuals529 / 62,512 0.008513 hom
Admixed American454 / 60,030 0.00764 hom
Middle Eastern21 / 6,062 0.00351 hom
South Asian37 / 91,080 0.000411 hom
European (non-Finnish)202 / 1,180,032 0.00017
East Asian2 / 44,878 4.5e-05
European (Finnish)1 / 64,044 1.6e-05
0 alternate alleles recorded in 2 other groups: Amish, Ashkenazi Jewish.

gnomAD v2.1

AF 0.012 · 3311 / 282,808 alleles · 195 hom · FAF 0.12
African/African American3052 / 24,962 0.12193 hom
Admixed American194 / 35,438 0.00552 hom
Remaining individuals33 / 7,224 0.0046
South Asian6 / 30,616 0.0002
European (non-Finnish)24 / 129,132 0.00019
East Asian2 / 19,948 0.0001
0 alternate alleles recorded in 2 other groups: Ashkenazi Jewish, European (Finnish).

gnomAD-Canada

AF 0.0086 · 159 / 18,418 alleles · 11 hom · FAF 0.12
afr143 / 1,020 0.1411 hom
oth8 / 1,138 0.007
amr5 / 838 0.006
nfe3 / 11,740 0.00026
0 alternate alleles recorded in 5 other groups: asj, eas, fin, mid, sas.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.00631039; MAF= 0.63104%, 10186/1614164 alleles, homozygotes = 596) and has highest observed frequency in the African/African American population (AF= 0.11919; MAF= 11.91905%, 8940/75006 alleles, homozygotes = 577); grpmax FAF= 0.117124.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.0117076; MAF= 1.17076%, 3311/282808 alleles, homozygotes = 195) and has highest observed frequency in the African/African American population (AF= 0.122266; MAF= 12.22658%, 3052/24962 alleles, homozygotes = 193); grpmax FAF= 0.1183.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00863286; MAF= 0.86329%, 159/18418 alleles, homozygotes = 11) and has highest observed frequency in the afr population (AF= 0.140196; grpmax FAF95= 0.121485).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +211 bp
0.000
SpliceAI acceptor gainat -281 bp
0.000
SpliceAI donor lossat -262 bp
0.000
SpliceAI donor gainat +349 bp
0.010
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.070
BayesDel
Not available

How the predictions were used

PP3 Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a max delta score of 0.01, and the REVEL score is 0.07, well below the DICER1 PP3 missense threshold of >=0.750. Details ▾Hide ▴
Rule
Requires qualifying damaging computational evidence under the DICER1 specification.
Evidence considered
  • SpliceAI max delta 0.01
  • REVEL 0.07
Still missing
  • If desired
  • additional splice predictor concordance such as MaxEntScan
Sources
BP4 Available computational evidence argues against a splice-disrupting effect, with SpliceAI max delta score 0.01 and REVEL 0.07, but the DICER1 specification for synonymous/non-coding BP4 calls for concordance of MaxEntScan and SpliceAI. MaxEntScan output was not identified, so BP4 was not fully established. Details ▾Hide ▴
Rule
For synonymous variants, BP4 requires concordance of MaxEntScan and SpliceAI showing no splicing effect.
Evidence considered
  • SpliceAI max delta 0.01
  • REVEL 0.07
  • No MaxEntScan output identified
Still missing
  • MaxEntScan result to confirm required predictor concordance for synonymous BP4
Sources
BP7 This is a synonymous variant, but the DICER1 BP7 rule requires BP4 and also no evidence that the nucleotide is highly conserved. BP4 was not fully established because the required MaxEntScan result was not identified, and no conservation assessment was identified. Details ▾Hide ▴
Rule
BP7 applies to silent variants only if BP4 is met and conservation does not argue against benignity.
Evidence considered
  • Synonymous consequence p.(Ala1560=)
  • SpliceAI max delta 0.01
  • No MaxEntScan or conservation assessment identified
Still missing
  • MaxEntScan result for BP4 prerequisite
  • Conservation assessment for the altered nucleotide
Sources

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.07.

6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    Richards S et al. · 2015
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
    Karbassi I et al. · 2016
    No paper-specific finding is recorded.
    PMID 26467025 ↗
  • American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
    Lu KH et al. · 2014
    No paper-specific finding is recorded.
    PMID 24493721 ↗
  • DICER1-Related Tumor Predisposition.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 24761742 ↗
  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    No paper-specific finding is recorded.
    PMID 25394175 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    No paper-specific finding is recorded.
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.00631039; MAF= 0.63104%, 10186/1614164 alleles, homozygotes = 596) and has highest observed frequency in the African/African American population (AF= 0.11919; MAF= 11.91905%, 8940/75006 alleles, homozygotes = 577); grpmax FAF= 0.117124.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.0117076; MAF= 1.17076%, 3311/282808 alleles, homozygotes = 195) and has highest observed frequency in the African/African American population (AF= 0.122266; MAF= 12.22658%, 3052/24962 alleles, homozygotes = 193); grpmax FAF= 0.1183.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00863286; MAF= 0.86329%, 159/18418 alleles, homozygotes = 11) and has highest observed frequency in the afr population (AF= 0.140196; grpmax FAF95= 0.121485).

ClinVar

This variant has been reported in ClinVar as Benign (11 clinical laboratories) and as benign (1 clinical laboratory). (ClinVarID = 261925)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.07.

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.