NM_177438.3:c.5248G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. BP4PM1_SupportingPM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.5248G>A variant in DICER1 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 1750 (p.Val1750Ile). This variant has an allele frequency of 0.000004221 (1/236924 alleles) across gnomAD v2.1.1 (non-cancer) with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.304; MaxEntScan and SpliceAI: no effect on splicing) (BP4). This variant resides within the RNase IIIb mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID:31342592). Due to conflicting evidence, this variant is classified as a variant of unknown significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM1_supporting, PM2_supporting, BP4. (Bayesian Points: 1; VCEP specifications version 1.2.0; 08/22/23) LINK:https://erepo.genome.network/evrepo/ui/classification/CA390865129/MONDO:0100216/024

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DICER1
NM_177438.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:3

Conservation

PhyloP100: 7.50

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

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

PM2

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

BP4

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.5248G>A	p.Val1750Ile	missense_variant	Exon 24 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.5248G>A	p.Val1750Ile	missense_variant	Exon 24 of 27	1	NM_177438.3	ENSP00000343745.3		Q9UPY3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251462

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135896

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:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

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:

0.0000187

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

DICER1-related tumor predisposition

Uncertain:2

Aug 22, 2023

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.5248G>A variant in DICER1 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 1750 (p.Val1750Ile). This variant has an allele frequency of 0.000004221 (1/236924 alleles) across gnomAD v2.1.1 (non-cancer) with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.304; MaxEntScan and SpliceAI: no effect on splicing) (BP4). This variant resides within the RNase IIIb mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). Due to conflicting evidence, this variant is classified as a variant of unknown significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM1_supporting, PM2_supporting, BP4. (Bayesian Points: 1; VCEP specifications version 1.2.0; 08/22/23) -

Oct 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1750 of the DICER1 protein (p.Val1750Ile). This variant is present in population databases (no rsID available, gnomAD 0.004%). 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: 477250). 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. 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:1

Jan 28, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V1750I variant (also known as c.5248G>A), located in coding exon 23 of the DICER1 gene, results from a G to A substitution at nucleotide position 5248. The valine at codon 1750 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Benign

0.25

BayesDel_addAF

Uncertain

0.094

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.38

T;T;T;T;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

.;.;D;.;D;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.47

T;T;T;T;T;T

MetaSVM

Uncertain

-0.024

MutationAssessor

Uncertain

2.2

M;M;M;M;.;M

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.93

N;N;N;N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.050

D;D;D;D;D;D

Sift4G

Uncertain

0.027

D;D;D;D;D;D

Polyphen

0.99

D;D;D;D;.;.

Vest4

0.56

MutPred

0.51

Loss of phosphorylation at Y1754 (P = 0.1997);Loss of phosphorylation at Y1754 (P = 0.1997);Loss of phosphorylation at Y1754 (P = 0.1997);Loss of phosphorylation at Y1754 (P = 0.1997);.;Loss of phosphorylation at Y1754 (P = 0.1997);

MVP

0.70

MPC

2.2

ClinPred

0.80

GERP RS

5.3

Varity_R

0.47

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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