chr14-95126651-G-A

Position:

chr14-95126651-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP5BP4BS2

The ENST00000343455.8(DICER1):c.832C>T(p.Leu278Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000042 in 1,427,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L278L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

DICER1
ENST00000343455.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 6.00

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 Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DICER1. . Gene score misZ 4.2261 (greater than the threshold 3.09). Trascript score misZ 6.1353 (greater than threshold 3.09). GenCC has associacion of gene with goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome, DICER1-related tumor predisposition, DICER1 syndrome, pleuropulmonary blastoma.

PP5

Variant 14-95126651-G-A is Pathogenic according to our data. Variant chr14-95126651-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 254354.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2}.

BP4

Computational evidence support a benign effect (MetaRNN=0.42307368). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DICER1	NM_177438.3 linkuse as main transcript	c.832C>T	p.Leu278Phe	missense_variant	7/27	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.832C>T	p.Leu278Phe	missense_variant	7/27	1	NM_177438.3	ENSP00000343745	P1	Q9UPY3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251224

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135804

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000420

AC:

AN:

1427018

Hom.:

Cov.:

AF XY:

0.00000702

AC XY:

AN XY:

712090

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:

0.0000701

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

DICER1-related tumor predisposition

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2023	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. 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 not expected to disrupt DICER1 protein function. ClinVar contains an entry for this variant (Variation ID: 254354). This missense change has been observed in individual(s) with pleuropulmonary blastoma (PMID: 26925222). This variant is present in population databases (rs768248216, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 278 of the DICER1 protein (p.Leu278Phe). -
Pathogenic, criteria provided, single submitter	clinical testing	International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota	Nov 10, 2014	- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 08, 2024

The p.L278F variant (also known as c.832C>T), located in coding exon 6 of the DICER1 gene, results from a C to T substitution at nucleotide position 832. The leucine at codon 278 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been reported as a germline mosaic finding in 1/124 children with pleuropulmonary blastoma (Brenneman M et al. F1000Res, 2015 Jul;4:214). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.53

D;D;D;D;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

.;.;D;.;D

M_CAP

Benign

0.046

MetaRNN

Benign

0.42

T;T;T;T;T

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.1

M;M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.4

N;N;N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.043

D;D;D;D;D

Sift4G

Benign

0.14

T;T;T;T;T

Polyphen

1.0

D;D;D;D;.

Vest4

0.52

MutPred

0.47

Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);

MVP

0.59

MPC

1.5

ClinPred

0.90

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.47

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