rs772431718

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The NM_177438.3(DICER1):c.919C>T(p.Arg307Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,612,746 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R307H) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

DICER1
NM_177438.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.44

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 -5 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.36765373).

BP6

Variant 14-95124653-G-A is Benign according to our data. Variant chr14-95124653-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 477294.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS2

High AC in GnomAdExome4 at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3 linkuse as main transcript	c.919C>T	p.Arg307Cys	missense_variant	8/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8 linkuse as main transcript	c.919C>T	p.Arg307Cys	missense_variant	8/27	1	NM_177438.3	P1	Q9UPY3-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000610

AC:

AN:

245978

Hom.:

AF XY:

0.0000450

AC XY:

AN XY:

133408

show subpopulations

Gnomad AFR exome

AF:

0.0000632

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000274

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.0000329

AC:

AN:

1460680

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

726636

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000661

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2023

The p.R307C variant (also known as c.919C>T), located in coding exon 7 of the DICER1 gene, results from a C to T substitution at nucleotide position 919. The arginine at codon 307 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well 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. -

DICER1-related tumor predisposition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

T;T;T;T;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

.;.;D;.;D

M_CAP

Benign

0.031

MetaRNN

Benign

0.37

T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.2

L;L;L;L;L

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.75

N;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.067

T;T;T;T;T

Sift4G

Benign

0.13

T;T;T;T;D

Polyphen

0.99

D;D;D;D;.

Vest4

0.57

MutPred

0.65

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);

MVP

0.71

MPC

1.4

ClinPred

0.19

GERP RS

5.6

Varity_R

0.15

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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