rs762677393

Positions:

chr14-95099797-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BS2_SupportingBP4

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.4189T>C variant in DICER1 is a missense variant predicted to cause substitution of tryptophan by arginine at amino acid 1397 (p.Trp1397Arg). The highest population minor allele frequency in gnomAD v3.1.2 is 0.00002462 (1/40622 alleles) in African/African American population (PM2_Supporting, BS1, and BA1 are not met). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors: 61756, 500031). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.207; MaxEntScan and SpliceAI: no effect on splicing) (BP4). 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: BS2_supporting; BP4. (Bayesian Points: -2; VCEP specifications version 1.2.0; 01/09/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA7330936/MONDO:0100216/024

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

DICER1
NM_177438.3 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:6B:1

Conservation

PhyloP100: 8.89

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

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.4189T>C	p.Trp1397Arg	missense_variant	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.4189T>C	p.Trp1397Arg	missense_variant	22/27	1	NM_177438.3	ENSP00000343745.3		Q9UPY3-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251096

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461514

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727054

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:

0.0000188

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151256

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73826

show subpopulations

Gnomad4 AFR

AF:

0.0000244

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:6Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2016	This variant is denoted DICER1 c.4189T>C at the cDNA level, p.Trp1397Arg (W1397R) at the protein level, and results in the change of a Tryptophan to an Arginine (TGG>CGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. DICER1 Trp1397Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tryptophan and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. DICER1 Trp1397Arg occurs at a position that is conserved in mammals and is located in the RNase III 1 domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether DICER1 Trp1397Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 27, 2021	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 27, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 15, 2023	The p.W1397R variant (also known as c.4189T>C), located in coding exon 21 of the DICER1 gene, results from a T to C substitution at nucleotide position 4189. The tryptophan at codon 1397 is replaced by arginine, an amino acid with dissimilar properties. In a study of DICER1 variants in 9173 exomes from The Cancer Genome Atlas and 175 exomes from the Therapeutically Applicable Research to Generate Effective Treatment, this variant was reported in a patient with endometrial cancer (Kim J et al. Mol Genet Genomic Med, 2019 03;7:e555). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

DICER1-related tumor predisposition

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1397 of the DICER1 protein (p.Trp1397Arg). This variant is present in population databases (rs762677393, gnomAD 0.002%). This missense change has been observed in individual(s) with endometrial cancer (PMID: 30672147). ClinVar contains an entry for this variant (Variation ID: 242101). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DICER1 protein function with a negative predictive value of 80%. 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. -
Likely benign, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	Jan 09, 2024	The NM_177438.2:c.4189T>C variant in DICER1 is a missense variant predicted to cause substitution of tryptophan by arginine at amino acid 1397 (p.Trp1397Arg). The highest population minor allele frequency in gnomAD v3.1.2 is 0.00002462 (1/40622 alleles) in African/African American population (PM2_Supporting, BS1, and BA1 are not met). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors: 61756, 500031). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.207; MaxEntScan and SpliceAI: no effect on splicing) (BP4). 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: BS2_supporting; BP4. (Bayesian Points: -2; VCEP specifications version 1.2.0; 01/09/2024) -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.28

T;T;T;T;.;.

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.64

.;.;T;.;T;T

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.23

T;T;T;T;T;T

MetaSVM

Uncertain

0.077

MutationAssessor

Benign

1.4

L;L;L;L;.;L

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.81

N;N;N;N;N;N

REVEL

Benign

0.21

Sift

Benign

0.040

D;D;D;D;T;D

Sift4G

Benign

0.18

T;T;T;T;T;T

Polyphen

0.13

B;B;B;B;.;.

Vest4

0.52

MutPred

0.28

Gain of disorder (P = 0.066);Gain of disorder (P = 0.066);Gain of disorder (P = 0.066);Gain of disorder (P = 0.066);.;Gain of disorder (P = 0.066);

MVP

0.94

MPC

1.4

ClinPred

0.62

GERP RS

5.8

Varity_R

0.25

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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