rs1555372646

chr14-95115805-C-Achr14-95115805-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_177438.3(DICER1):c.1769G>T(p.Cys590Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. C590S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.66

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DICER1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.779

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.1769G>T	p.Cys590Phe	missense_variant	11/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.1769G>T	p.Cys590Phe	missense_variant	11/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DICER1-related tumor predisposition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 21, 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: 483419). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 590 of the DICER1 protein (p.Cys590Phe). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2023

The p.C590F variant (also known as c.1769G>T), located in coding exon 10 of the DICER1 gene, results from a G to T substitution at nucleotide position 1769. The cysteine at codon 590 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.82	D;D;D;D;.
Eigen	Benign	0.088
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D
REVEL	Uncertain	0.35
Sift	Benign	0.043	D;D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D;D
Polyphen		0.13	B;B;B;B;.
Vest4		0.93
MutPred		0.30		Loss of methylation at K589 (P = 0.0427);Loss of methylation at K589 (P = 0.0427);Loss of methylation at K589 (P = 0.0427);Loss of methylation at K589 (P = 0.0427);Loss of methylation at K589 (P = 0.0427);
MVP		0.93
MPC		1.2
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.77
gMVP		0.84

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: rs1555372646; hg19: chr14-95582142;