14-95117750-T-C

Position:

chr14-95117750-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BS2BA1BP4

This summary comes from the ClinGen Evidence Repository: The NM_177438.3:c.1381A>G variant in DICER1 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 461 (p.Ile461Val). The highest population minor allele frequency in gnomAD v4.1.0 is 0.005261 (32/6082 alleles) in the Middle Eastern 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-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BA1. (Bayesian Points: NA; VCEP specifications version 1.3.0; 06/25/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA7331487/MONDO:0100216/024

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

DICER1
NM_177438.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:7

Conservation

PhyloP100: 7.92

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

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

BS2

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

BA1

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 link	c.1381A>G	p.Ile461Val	missense_variant	9/27	ENST00000343455.8	NP_803187.1	Q9UPY3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8 link	c.1381A>G	p.Ile461Val	missense_variant	9/27	1	NM_177438.3	ENSP00000343745.3		Q9UPY3-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152202

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:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000179

AC:

AN:

251200

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000163

AC:

238

AN:

1461560

Hom.:

Cov.:

AF XY:

0.000195

AC XY:

142

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000406

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000132

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74366

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:

0.000191

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000197

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000655

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 04, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with pituitary macroadenoma (Martnez de LaPiscina et al., 2020); This variant is associated with the following publications: (PMID: 21266384, 34313605, 35384518, 32714280) -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 19, 2023	- -

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, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	Jun 25, 2024	The NM_177438.3:c.1381A>G variant in DICER1 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 461 (p.Ile461Val). The highest population minor allele frequency in gnomAD v4.1.0 is 0.005261 (32/6082 alleles) in the Middle Eastern 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-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BA1. (Bayesian Points: NA; VCEP specifications version 1.3.0; 06/25/2024) -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 20, 2021	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. -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

T;T;T;T;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

.;.;D;.;D

M_CAP

Benign

0.031

MetaRNN

Benign

0.35

T;T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.96

L;L;L;L;L

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.84

N;N;N;N;N

REVEL

Benign

0.29

Sift

Benign

0.10

T;T;T;T;T

Sift4G

Benign

0.19

T;T;T;T;D

Polyphen

0.84

P;P;P;P;.

Vest4

0.76

MVP

0.67

MPC

1.0

ClinPred

0.11

GERP RS

5.2

Varity_R

0.32

gMVP

0.44

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