rs139786661

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS1BS2BP4

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.3428T>C variant in DICER1 is a missense variant predicted to cause substitution of leucine by proline at amino acid 1143 (p.Leu1143Pro). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; GTRs: 500031, 61756). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0029 (69/23442 alleles; FAF=0.0020) in African/African-American population, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.102, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). In summary, this variant meets the criteria to be classified as BENIGN for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2, BS1, BP4. (Bayesian Points: -9; VCEP specifications version 1; 02/11/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA349475/MONDO:0017288/024

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

DICER1
NM_177438.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:11

Conservation

PhyloP100: 1.75

Publications

2 publications found

Variant links:

Genes affected

DICER1 (HGNC:17098): (dicer 1, ribonuclease III) This gene encodes a protein possessing an RNA helicase motif containing a DEXH box in its amino terminus and an RNA motif in the carboxy terminus. The encoded protein functions as a ribonuclease and is required by the RNA interference and small temporal RNA (stRNA) pathways to produce the active small RNA component that represses gene expression. This protein also acts as a strong antiviral agent with activity against RNA viruses, including the Zika and SARS-CoV-2 viruses. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2021]

DICER1 Gene-Disease associations (from GenCC):

DICER1-related tumor predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
pleuropulmonary blastoma
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
DICER1 syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

DICER1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3 link	c.3428T>C	p.Leu1143Pro	missense_variant	Exon 21 of 27	ENST00000343455.8	NP_803187.1	Q9UPY3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8 link	c.3428T>C	p.Leu1143Pro	missense_variant	Exon 21 of 27	1	NM_177438.3	ENSP00000343745.3		Q9UPY3-1

Frequencies

GnomAD3 genomes

AF:

0.000677

AC:

103

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000171

AC:

AN:

250930

AF XY:

0.0000958

show subpopulations

Gnomad AFR exome

AF:

0.00261

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000828

AC:

121

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00296

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112006

Other (OTH)

AF:

0.000248

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000689

AC:

105

AN:

152326

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00245

AC:

102

AN:

41574

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000329

Hom.:

Bravo

AF:

0.000748

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:4

Apr 28, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DICER1: BP4, BS1 -

Oct 08, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 07, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DICER1-related tumor predisposition

Benign:3

May 18, 2022

ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_177438.2:c.3428T>C variant in DICER1 is a missense variant predicted to cause substitution of leucine by proline at amino acid 1143 (p.Leu1143Pro). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; GTRs: 500031, 61756). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0029 (69/23442 alleles; FAF=0.0020) in African/African-American population, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.102, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). In summary, this variant meets the criteria to be classified as BENIGN for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2, BS1, BP4. (Bayesian Points: -9; VCEP specifications version 1; 02/11/2022) -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 10, 2020

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3428T>C (p.Leu1143Pro) missense variant has a frequency of 0.0002586 (73 of 282,336 alleles) in gnomAD v2.1.1 with a maximum allele frequency of 0.002904 (72 of 24,794) in the African subpopulation (http://gnomad.broadinstitute.org). This is greater than the expected prevalence of a DICER1 pathogenic variant (BS1, PMID: 24761742). DICER1 has a missense z-score of >3.09 which suggests that this gene has a low rate of benign missense variation and that missense variants are more likely to be damaging (PP2). However, five of seven in silico tools predict a benign effect of this variant on protein function (BP4). This variant has been reported somatically in a case of pediatric acute myeloid leukemia (PMID: 29227476), but to our knowledge, this variant has not been reported in individuals with a personal or family history suggestive of DICER1 Tumor Predisposition syndrome (internal data and literature review). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP4, PP2. -

Hereditary cancer-predisposing syndrome

Benign:2

Apr 14, 2021

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Apr 24, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified

Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DICER1-related disorder

Benign:1

Nov 22, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.22

T;T;T;T;.;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.56

.;.;T;.;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.0065

T;T;T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.0

L;L;L;L;.;L

PhyloP100

1.7

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.31

N;N;N;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.24

T;T;T;T;T;T

Sift4G

Benign

0.31

T;T;T;T;T;T

Polyphen

0.0

B;B;B;B;.;.

Vest4

0.23

MVP

0.70

MPC

0.79

ClinPred

0.018

GERP RS

-1.4

Varity_R

0.076

gMVP

0.61

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over