14-95096637-A-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BS2_SupportingBP4

This summary comes from the ClinGen Evidence Repository: NM_177438.3(DICER1):c.4283T>A variant in DICER1 is a missense variant predicted to cause substitution of methionine by lysine at amino acid 1428 (p.Met1802Lys). This variant received a total of 0.5 phenotype points in a single proband (PS4 not met; Internal lab contributors SCV001509541.1). This variant has also been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors SCV001509541.1, SCV001444307.1). The highest population minor allele frequency in gnomAD v2.1.1 non-cancer is 0.00008606 (3/34860 alleles) in Latino/Admixed American population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.115; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1 syndrome 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/CA16614307/MONDO:0100216/024

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

DICER1
NM_177438.3 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:4B:1

Conservation

PhyloP100: 0.102

Publications

0 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: Likely_benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177438.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DICER1	NM_177438.3	MANE Select	c.4283T>A	p.Met1428Lys	missense	Exon 23 of 27	NP_803187.1
DICER1	NM_001271282.3		c.4283T>A	p.Met1428Lys	missense	Exon 23 of 27	NP_001258211.1
DICER1	NM_001291628.2		c.4283T>A	p.Met1428Lys	missense	Exon 23 of 27	NP_001278557.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DICER1	ENST00000343455.8	TSL:1 MANE Select	c.4283T>A	p.Met1428Lys	missense	Exon 23 of 27	ENSP00000343745.3
DICER1	ENST00000393063.6	TSL:1	c.4283T>A	p.Met1428Lys	missense	Exon 25 of 29	ENSP00000376783.1
DICER1	ENST00000527414.5	TSL:1	c.4283T>A	p.Met1428Lys	missense	Exon 23 of 27	ENSP00000435681.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

247190

AF XY:

0.0000149

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000874

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1459992

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726258

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33372

American (AMR)

AF:

0.0000898

AC:

AN:

44552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26030

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

85892

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1111066

Other (OTH)

AF:

0.00

AC:

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000282

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Oct 02, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

Jul 24, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M1428K variant (also known as c.4283T>A), located in coding exon 22 of the DICER1 gene, results from a T to A substitution at nucleotide position 4283. The methionine at codon 1428 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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

Jan 09, 2024

ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

NM_177438.3(DICER1):c.4283T>A variant in DICER1 is a missense variant predicted to cause substitution of methionine by lysine at amino acid 1428 (p.Met1802Lys). This variant received a total of 0.5 phenotype points in a single proband (PS4 not met; Internal lab contributors SCV001509541.1). This variant has also been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors SCV001509541.1, SCV001444307.1). The highest population minor allele frequency in gnomAD v2.1.1 non-cancer is 0.00008606 (3/34860 alleles) in Latino/Admixed American population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.115; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1 syndrome 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)

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 1428 of the DICER1 protein (p.Met1428Lys). This variant is present in population databases (no rsID available, gnomAD 0.009%). 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: 412118). 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.

not provided

Uncertain:1

May 10, 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 does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.24

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.83

M_CAP

Benign

0.045

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.5

PhyloP100

0.10

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.39

REVEL

Benign

0.12

Sift

Benign

0.034

Sift4G

Benign

0.23

Polyphen

0.0030

Vest4

0.49

MutPred

0.46

Gain of ubiquitination at M1428 (P = 0.0054)

MVP

0.75

MPC

0.81

ClinPred

0.027

GERP RS

-1.4

Varity_R

0.27

gMVP

0.55

Mutation Taster

=79/21

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over