rs756586319

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.527A>T variant in DICER1 is a missense variant predicted to cause substitution of glutamic acid by valine at amino acid 176 (p.Glu176Val). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000001695 (2/1179702 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.835) (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PP3. (Bayesian Points: 1; VCEP specifications version 1.3.0; 02/27/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA7331646/MONDO:0100216/024

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DICER1
NM_177438.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4

Conservation

PhyloP100: 7.61

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 Uncertain_significance. Variant got 1 ACMG points.

PP3

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.527A>T	p.Glu176Val	missense_variant	Exon 5 of 27	ENST00000343455.8	NP_803187.1	Q9UPY3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8 link	c.527A>T	p.Glu176Val	missense_variant	Exon 5 of 27	1	NM_177438.3	ENSP00000343745.3		Q9UPY3-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251082

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135716

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461208

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726932

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:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

DICER1-related tumor predisposition

Uncertain:2

Feb 27, 2024

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.527A>T variant in DICER1 is a missense variant predicted to cause substitution of glutamic acid by valine at amino acid 176 (p.Glu176Val). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000001695 (2/1179702 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.835) (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PP3. (Bayesian Points: 1; VCEP specifications version 1.3.0; 02/27/2024) -

Jan 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 176 of the DICER1 protein (p.Glu176Val). This variant is present in population databases (rs756586319, gnomAD 0.002%). 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: 543562). 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 expected to disrupt DICER1 protein function with a positive 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. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Nov 17, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E176V variant (also known as c.527A>T), located in coding exon 4 of the DICER1 gene, results from an A to T substitution at nucleotide position 527. The glutamic acid at codon 176 is replaced by valine, an amino acid with dissimilar properties. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;D;D;D;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

.;.;D;.;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

4.1

H;H;H;H;H

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.3

D;D;D;D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D;D

Polyphen

0.0090

B;B;B;B;.

Vest4

0.96

MutPred

0.88

Loss of catalytic residue at E176 (P = 0.1593);Loss of catalytic residue at E176 (P = 0.1593);Loss of catalytic residue at E176 (P = 0.1593);Loss of catalytic residue at E176 (P = 0.1593);Loss of catalytic residue at E176 (P = 0.1593);

MVP

0.99

MPC

0.59

ClinPred

0.98

GERP RS

5.8

Varity_R

0.91

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.30

Position offset: -21

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