chr14-95099805-G-GTGT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. BS2PM4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.4178_4180dup variant is predicted to cause a change in the length of the protein (p.Asn1393dup) due to an in-frame insertion of 1 amino acid in a non-repeat region outside of the RNase IIIb domain (p.D606-p.D609; p.E1418-p.E1420; p.E1422-p.E1425) (PM4_Supporting). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; Internal lab contributors). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00004417 (3/67924 alleles) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM4_Supporting, BS2. (Bayesian Points: -3; VCEP specifications version 1.3.0; 08/27/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10583198/MONDO:0017288/024

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

DICER1
NM_177438.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign reviewed by expert panel U:4B:3

Conservation

PhyloP100: -0.571

Publications

1 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: Likely_benign. The variant received -3 ACMG points.

PM4

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

BS2

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177438.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DICER1	NM_177438.3	MANE Select	c.4178_4180dupACA	p.Asn1393dup	conservative_inframe_insertion	Exon 22 of 27	NP_803187.1
DICER1	NM_001271282.3		c.4178_4180dupACA	p.Asn1393dup	conservative_inframe_insertion	Exon 22 of 27	NP_001258211.1
DICER1	NM_001291628.2		c.4178_4180dupACA	p.Asn1393dup	conservative_inframe_insertion	Exon 22 of 27	NP_001278557.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DICER1	ENST00000343455.8	TSL:1 MANE Select	c.4178_4180dupACA	p.Asn1393dup	conservative_inframe_insertion	Exon 22 of 27	ENSP00000343745.3
DICER1	ENST00000393063.6	TSL:1	c.4178_4180dupACA	p.Asn1393dup	conservative_inframe_insertion	Exon 24 of 29	ENSP00000376783.1
DICER1	ENST00000527414.5	TSL:1	c.4178_4180dupACA	p.Asn1393dup	conservative_inframe_insertion	Exon 22 of 27	ENSP00000435681.1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151312

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461570

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111888

Other (OTH)

AF:

0.0000166

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

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:

0.0000198

AC:

AN:

151312

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73798

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41054

American (AMR)

AF:

0.00

AC:

AN:

15190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67924

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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:

0.00

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Oct 30, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DICER1 c.4178_4180dup (p.Asn1393dup) variant, also known as p.Asn1393_Thr1394insAsn, has been reported in the published literature in an individual with early onset thyroid carcinoma (PMID: 33630087 (2021)) and an individual with cutaneous melanoma (PMID: 39001563 (2021)). The frequency of this variant in the general population, 0.000044 (3/67924 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.

Jun 20, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In-frame duplication of 1 amino acid in a non-repeat region; Observed in an individual with follicular thyroid cancer (PMID: 33630087); This variant is associated with the following publications: (PMID: 38084291, 33630087)

DICER1-related tumor predisposition

Benign:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 27, 2024

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

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_177438.2:c.4178_4180dup variant is predicted to cause a change in the length of the protein (p.Asn1393dup) due to an in-frame insertion of 1 amino acid in a non-repeat region outside of the RNase IIIb domain (p.D606-p.D609; p.E1418-p.E1420; p.E1422-p.E1425) (PM4_Supporting). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; Internal lab contributors). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00004417 (3/67924 alleles) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM4_Supporting, BS2. (Bayesian Points: -3; VCEP specifications version 1.3.0; 08/27/2024)

Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome

Uncertain:1

Aug 21, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DICER1-related disorder

Uncertain:1

Jan 30, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DICER1 c.4178_4180dupACA variant is predicted to result in an in-frame duplication (p.Asn1393dup). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been classified as uncertain by an expert panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/242100/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Hereditary cancer-predisposing syndrome

Benign:1

Mar 11, 2025

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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.57

Mutation Taster

=60/40

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over