14-95103843-C-T

Position:

chr14-95103843-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS2BP4BS1

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.3553G>A variant in DICER1 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 1185 (p.Ala1185Thr). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; ClinVar SCV: SCV000661803.4, SCV000291663.10; PMIDs: 24728327). The highest population minor allele frequency in gnomAD v3.1.2 is 0.002 (45/15,076 alleles) in Latino/Admixed American populations, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.048; MaxEntScan and SpliceAI: no effect on splicing (BP4). 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: BS1, BS2, BP4. (Bayesian Points: -9; VCEP specifications version 1.2.0; 08/22/23) LINK:https://erepo.genome.network/evrepo/ui/classification/CA158273/MONDO:0100216/024

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 1 hom. )

Consequence

DICER1
NM_177438.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:5B:5O:1

Conservation

PhyloP100: 1.84

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 -9 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS1

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.3553G>A	p.Ala1185Thr	missense_variant	21/27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8 linkuse as main transcript	c.3553G>A	p.Ala1185Thr	missense_variant	21/27	1	NM_177438.3	ENSP00000343745	P1	Q9UPY3-1

Frequencies

GnomAD3 genomes

AF:

0.000441

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000175

AC:

AN:

251400

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000622

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.000917

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.000467

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000129

Hom.:

Bravo

AF:

0.000393

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:5Benign:5Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

DICER1-related tumor predisposition

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 07, 2020	The DICER1 c.3553G>A (p.Ala1185Thr) missense change has a maximum subpopulation frequency of 0.073% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/14-95570180-C-T). This is likely to be greater than the expected prevalence of a pathogenic variant in DICER1 (PMID: 24761742). This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533), and in silico tools do not agree on the effect of this variant on protein function. To our knowledge, this variant has not been reported in individuals with a personal or family history suggestive of DICER1 Tumor Predisposition syndrome (internal data and literature review). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP2. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	Aug 22, 2023	The NM_177438.2:c.3553G>A variant in DICER1 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 1185 (p.Ala1185Thr). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; ClinVar SCV: SCV000661803.4, SCV000291663.10; PMIDs: 24728327). The highest population minor allele frequency in gnomAD v3.1.2 is 0.002 (45/15,076 alleles) in Latino/Admixed American populations, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.048; MaxEntScan and SpliceAI: no effect on splicing (BP4). 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: BS1, BS2, BP4. (Bayesian Points: -9; VCEP specifications version 1.2.0; 08/22/23) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 03, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2019	The DICER1 c.3553G>A; p.Ala1185Thr variant (rs150514959), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 133970). This variant is found in the general population with an overall allele frequency of 0.02% (49/282800 alleles) in the Genome Aggregation Database. The alanine at codon 1185 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in healthy individuals undergoing whole genome sequencing (Bodian et al., 2014); This variant is associated with the following publications: (PMID: 24728327) -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 07, 2020	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 01, 2021	- -

DICER1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2022

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

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;T;T;T;.;.

Eigen

Benign

-0.15

Eigen_PC

Benign

0.079

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

.;.;D;.;D;D

M_CAP

Benign

0.036

MetaRNN

Benign

0.031

T;T;T;T;T;T

MetaSVM

Benign

-0.31

MutationAssessor

Benign

1.0

L;L;L;L;.;L

MutationTaster

Benign

0.67

D;D;D;D;D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

0.15

N;N;N;N;N;N

REVEL

Benign

0.048

Sift

Benign

0.21

T;T;T;T;T;T

Sift4G

Benign

0.71

T;T;T;T;T;T

Polyphen

0.0020

B;B;B;B;.;.

Vest4

0.25

MVP

0.78

MPC

0.48

ClinPred

0.013

GERP RS

5.6

Varity_R

0.057

gMVP

0.45

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