14-95117723-C-A

Position:

• chr14-95117723-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PP4 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.1408G>T (p.Glu470Ter) variant in DICER1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 9/27 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 family meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMIDs 26925222, 28323992, 30178239, 30339877). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1 syndrome (PP4, PMID 28323992). 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, PP4, PM2_supporting. (Bayesian Points: 11; VCEP specifications version 1; 02/11/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10586458/MONDO:0017288/024

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_177438.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.81

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 11 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.
• PP4: 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	c.1408G>T	p.Glu470Ter	stop_gained	9/27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.1408G>T	p.Glu470Ter	stop_gained	9/27	1	NM_177438.3	ENSP00000343745	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

DICER1-related tumor predisposition Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota	Nov 10, 2014	- -
Pathogenic, criteria provided, single submitter	curation	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Jul 01, 2019	ACMG criteria met: PVS1, PM2, PM7, PP4 -
Pathogenic, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	May 18, 2022	The NM_177438.2:c.1408G>T (p.Glu470Ter) variant in DICER1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 9/27 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 family meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMIDs 26925222, 28323992, 30178239, 30339877). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1 syndrome (PP4, PMID 28323992). 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, PP4, PM2_supporting. (Bayesian Points: 11; VCEP specifications version 1; 02/11/2022) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2021

The p.E470* pathogenic mutation (also known as c.1408G>T), located in coding exon 8 of the DICER1 gene, results from a G to T substitution at nucleotide position 1408. This changes the amino acid from a glutamic acid to a stop codon within coding exon 8. This alteration was identified in an individual with nodular hyperplasia of the thyroid (Khan NE et al. J Clin Endocrinol Metab, 2017 05;102:1614-1622). Additionally, this alteration was identified in a seven year old diagnosed with medulloepithelioma (Huryn LA et al. Ophthalmology, 2019 02;126:296-304). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.98
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs886037671; hg19: chr14-95584060;