rs1555366197

Variant names:

• chr14-95091250-AG-A
• rs1555366197
• NM_177438.3:c.5479delC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.5479del(p.Leu1827fs) variant in DICER1 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 25/27 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant received a total of 1 phenotype points across 1 proband with PPB, meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting, SCV000658348.1). This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting). In summary, this variant meets the criteria to be classified as PATHOGENIC for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PVS1, PS4_Supporting, PM2_Supporting. (Bayesian Points: 10; VCEP specifications version 1; 02/11/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA658656432/MONDO:0017288/024

• Frequency: Genomes: not found (cov: 33)
• Consequence: DICER1 NM_177438.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 2.21

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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	c.5479delC	p.Leu1827TrpfsTer11	frameshift_variant	Exon 25 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.5479delC	p.Leu1827TrpfsTer11	frameshift_variant	Exon 25 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

DICER1-related tumor predisposition Pathogenic:2

May 18, 2022

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

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_177438.2:c.5479del(p.Leu1827fs) variant in DICER1 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 25/27 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant received a total of 1 phenotype points across 1 proband with PPB, meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting, SCV000658348.1). This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting). In summary, this variant meets the criteria to be classified as PATHOGENIC for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PVS1, PS4_Supporting, PM2_Supporting. (Bayesian Points: 10; VCEP specifications version 1; 02/11/2022) -

Jun 17, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change deletes 1 nucleotide from exon 25 of the DICER1 mRNA (c.5479delC), causing a frameshift at codon 1827. This creates a premature translational stop signal (p.Leu1827Trpfs*11) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in DICER1 are known to be pathogenic (PMID: 19556464, 21266384). -

not provided Pathogenic:1

Mar 23, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555366197; hg19: chr14-95557587;