rs114947750

Positions:

chr14-95115749-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BA1BP4BS2

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.1825G>T variant in DICER1 is a missense variant predicted to cause substitution of Aspartic Acid by Tyrosine at amino acid 609 (p.Asp609Tyr). The highest population minor allele frequency in gnomAD non cancer dataset v2.1.1 is 0.006310 (149/23614 alleles) in the African population, which is higher than the ClinGen DICER1 VCEP threshold (>0.003) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BA1. (Bayesian Points: NA; VCEP specifications version 1; 02/11/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA158261/MONDO:0017288/024

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 2 hom. )

Consequence

DICER1
NM_177438.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:12O:1

Conservation

PhyloP100: 2.85

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

BS2

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3 linkuse as main transcript	c.1825G>T	p.Asp609Tyr	missense_variant	11/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8 linkuse as main transcript	c.1825G>T	p.Asp609Tyr	missense_variant	11/27	1	NM_177438.3	P1	Q9UPY3-1

Frequencies

GnomAD3 genomes

AF:

0.00167

AC:

254

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00572

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000501

AC:

126

AN:

251474

Hom.:

AF XY:

0.000405

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00658

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000237

AC:

347

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

156

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00684

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.00168

AC:

256

AN:

152292

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00575

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000345

Hom.:

Bravo

AF:

0.00222

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000626

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 06, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 29, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 19, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2021	This variant is associated with the following publications: (PMID: 23555315, 28007021, 24728327) -

DICER1-related tumor predisposition

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	May 18, 2022	The NM_177438.2:c.1825G>T variant in DICER1 is a missense variant predicted to cause substitution of Aspartic Acid by Tyrosine at amino acid 609 (p.Asp609Tyr). The highest population minor allele frequency in gnomAD non cancer dataset v2.1.1 is 0.006310 (149/23614 alleles) in the African population, which is higher than the ClinGen DICER1 VCEP threshold (>0.003) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BA1. (Bayesian Points: NA; VCEP specifications version 1; 02/11/2022) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 24, 2018	This alteration is classified as likely 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 06, 2020	- -

DICER1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

T;T;T;T;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.073

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

.;.;D;.;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.0089

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.0

L;L;L;L;L

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.93

N;N;N;N;N

REVEL

Benign

0.22

Sift

Uncertain

0.012

D;D;D;D;D

Sift4G

Uncertain

0.024

D;D;D;D;D

Polyphen

0.0010

B;B;B;B;.

Vest4

0.81

MVP

0.96

MPC

0.61

ClinPred

0.034

GERP RS

5.1

Varity_R

0.19

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

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