chr14-95090645-G-T

Variant names:

• chr14-95090645-G-T
• rs769490774
• NM_177438.3:c.5622C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.5622C>A (p.Tyr1874Ter) variant in DICER1 is a nonsense variant that may cause loss of function of the protein; however, it is predicted to escape nonsense-mediated decay and remove <10% of the protein (PVS1_Moderate). This variant is absent from gnomAD non-cancer datasets v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PVS1_moderate; PM2_supporting (Bayesian Points: 3; VCEP specifications version 1.1.0; 2/28/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA390863714/MONDO:0017288/024

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DICER1 NM_177438.3 stop_gained
• Clinical Significance: Uncertain significance reviewed by expert panel U:5 O:1
• Conservation: PhyloP100: -0.0770

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 Uncertain_significance. Variant got 3 ACMG points.

• PVS1: 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.5622C>A	p.Tyr1874*	stop_gained	Exon 27 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.5622C>A	p.Tyr1874*	stop_gained	Exon 27 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

DICER1-related tumor predisposition Uncertain:2 Other:1

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr1874*) in the DICER1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the DICER1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. ClinVar contains an entry for this variant (Variation ID: 648917). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Feb 28, 2023

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_177438.2:c.5622C>A (p.Tyr1874Ter) variant in DICER1 is a nonsense variant that may cause loss of function of the protein; however, it is predicted to escape nonsense-mediated decay and remove <10% of the protein (PVS1_Moderate). This variant is absent from gnomAD non-cancer datasets v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PVS1_moderate; PM2_supporting (Bayesian Points: 3; VCEP specifications version 1.1.0; 2/28/2023). -

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 07-29-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Hereditary cancer-predisposing syndrome Uncertain:2

Jun 08, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Aug 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y1874* variant (also known as c.5622C>A), located in coding exon 26 of the DICER1 gene, results from a C to A substitution at nucleotide position 5622. This changes the amino acid from a tyrosine to a stop codon within coding exon 26. This alteration occurs at the 3' terminus of theDICER1 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 49 amino acids of the protein. The exact functional effect of this alteration is unknown. This alteration was identified in 1/92,296 unselected patients undergoing DICER1 testing via whole genome analysis; this patient was described to be in her 20s and had no reported DICER1-associated features" (Mirshahi UL et al. JAMA Netw Open, 2021 02;4:e210112). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

May 26, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last 49 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Observed in an individual with no DICER1-related phenotype undergoing whole exome sequencing (Mirshahi et al., 2021); This variant is associated with the following publications: (PMID: 33630087) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	35
DANN	Benign	0.96
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.31	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Vest4		0.58
MutPred		0.63		Gain of MoRF binding (P = 0.0182);
MVP		0.76
ClinPred		0.56	D
GERP RS		-2.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: 18

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

Publications

LitVar

Other links and lift over

dbSNP: rs769490774; hg19: chr14-95556982;