rs749834289

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_177438.3:c.2417C>T variant in DICER1 is a missense variant predicted to cause substitution of threonine by methionine at amino acid 806 (p.Thr806Met). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; PMID:33630087; Internal lab contributors). 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). The total allele frequency in gnomAD v4.1.0 is 0.00001116(18/1613564 alleles) with a highest population minor allele frequency of 0.00003294 (3/91066 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.746, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting. (Bayesian Points: -1; VCEP specifications version 1.3.0; 01/07/2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA7331249/MONDO:0100216/024

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

DICER1
NM_177438.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:5

Conservation

PhyloP100: 9.63

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

DICER1-related tumor predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
pleuropulmonary blastoma
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
DICER1 syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

DICER1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received -1 ACMG points.

BS2

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 link	c.2417C>T	p.Thr806Met	missense_variant	Exon 15 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8 link	c.2417C>T	p.Thr806Met	missense_variant	Exon 15 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151754

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251324

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461810

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111970

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151754

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74078

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41256

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67988

Other (OTH)

AF:

0.000480

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

DICER1-related tumor predisposition

Uncertain:2

Jan 07, 2025

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_177438.3:c.2417C>T variant in DICER1 is a missense variant predicted to cause substitution of threonine by methionine at amino acid 806 (p.Thr806Met). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; PMID: 33630087; Internal lab contributors). 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). The total allele frequency in gnomAD v4.1.0 is 0.00001116(18/1613564 alleles) with a highest population minor allele frequency of 0.00003294 (3/91066 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.746, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting. (Bayesian Points: -1; VCEP specifications version 1.3.0; 01/07/2025) -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 806 of the DICER1 protein (p.Thr806Met). This variant is present in population databases (rs749834289, gnomAD 0.006%). 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: 412136). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DICER1 protein function with a negative predictive value of 95%. 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. -

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

Uncertain:1

Dec 08, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Apr 25, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colon cancer and other cancers (Mirshahi 2021); This variant is associated with the following publications: (PMID: 33630087) -

Hereditary cancer-predisposing syndrome

Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T806M variant (also known as c.2417C>T), located in coding exon 14 of the DICER1 gene, results from a C to T substitution at nucleotide position 2417. The threonine at codon 806 is replaced by methionine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;D;D;D;.

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;.;D;.;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.85

D;D;D;D;D

MetaSVM

Uncertain

0.31

MutationAssessor

Uncertain

2.2

M;M;M;M;M

PhyloP100

9.6

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-4.3

D;D;D;D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0

D;D;D;D;.

Vest4

0.86

MutPred

0.50

Loss of phosphorylation at T806 (P = 0.0654);Loss of phosphorylation at T806 (P = 0.0654);Loss of phosphorylation at T806 (P = 0.0654);Loss of phosphorylation at T806 (P = 0.0654);Loss of phosphorylation at T806 (P = 0.0654);

MVP

0.97

MPC

1.4

ClinPred

0.74

GERP RS

5.7

Varity_R

0.59

gMVP

0.88

Mutation Taster

=25/75

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over