Variant rs878855263 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -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:2

Conservation

PhyloP100: -0.571

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 links:

DICER1 (HGNC:):

DICER1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DICER1	NM_177438.3 linkuse as main transcript	c.4178_4180dupACA	p.Asn1393dup	conservative_inframe_insertion	22/27	ENST00000343455.8	NP_803187.1	Q9UPY3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8 linkuse as main transcript	c.4178_4180dupACA	p.Asn1393dup	conservative_inframe_insertion	22/27	1	NM_177438.3	ENSP00000343745.3		Q9UPY3-1

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151312

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73798

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

DICER1-related tumor predisposition

Benign:2

Likely benign, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	Aug 27, 2024	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) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 21, 2023

- -

DICER1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2023

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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 20, 2024

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) -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2023

The c.4178_4180dupACA variant (also known as p.N1393dup), located in coding exon 21 of the DICER1 gene, results from an in-frame duplication of ACA at nucleotide positions 4178 to 4180. This results in the duplication of an extra asparagine residue between codons 1393 and 1394. This variant, designated p.Asn1393_1394insAsn, has been reported in a patient with follicular thyroid carcinoma in her 20s (Mirshahi UL et al. JAMA Netw Open, 2021 Feb;4:e210112). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over