rs754352488

chr14-95103548-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_177438.3(DICER1):c.3848T>C(p.Ile1283Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1283V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.00600

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DICER1
• BP4: Computational evidence support a benign effect (MetaRNN=0.047151).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.3848T>C	p.Ile1283Thr	missense_variant	21/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.3848T>C	p.Ile1283Thr	missense_variant	21/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251310 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000547 AC: 8 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

DICER1-related tumor predisposition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 04, 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: 242093). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. This variant is present in population databases (rs754352488, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1283 of the DICER1 protein (p.Ile1283Thr). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2020

The p.I1283T variant (also known as c.3848T>C), located in coding exon 20 of the DICER1 gene, results from a T to C substitution at nucleotide position 3848. The isoleucine at codon 1283 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	2.1
Dann	Benign	0.54
DEOGEN2	Benign	0.22	T;T;T;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.016	N
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.047	T;T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.2	L;L;L;L;.;L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.10	N;N;N;N;N;N
REVEL	Benign	0.041
Sift	Benign	0.55	T;T;T;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;.;.
Vest4		0.13
MutPred		0.44		Gain of glycosylation at I1283 (P = 0.012);Gain of glycosylation at I1283 (P = 0.012);Gain of glycosylation at I1283 (P = 0.012);Gain of glycosylation at I1283 (P = 0.012);.;Gain of glycosylation at I1283 (P = 0.012);
MVP		0.43
MPC		0.62
ClinPred		0.013	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.019
gMVP		0.21

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

Other links and lift over

dbSNP: rs754352488; hg19: chr14-95569885;