14-95093995-C-T

Position:

• chr14-95093995-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. BP4 PM1_Supporting BS2_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.5257G>A variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 1753 (p.Asp1753Asn). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.431; 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). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; GTR ID: 500031, 61756). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4, PM1_Supporting, BS2_Supporting. (Bayesian Points: 0; VCEP specifications version 1.2.0; 08/22/23) LINK:https://erepo.genome.network/evrepo/ui/classification/CA390865107/MONDO:0100216/024

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: DICER1 ENST00000343455.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:6
• Conservation: PhyloP100: 7.50

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 0 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.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DICER1	NM_177438.3	c.5257G>A	p.Asp1753Asn	missense_variant	24/27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.5257G>A	p.Asp1753Asn	missense_variant	24/27	1	NM_177438.3	ENSP00000343745	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461848 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 21, 2023	This variant has not been reported in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

DICER1-related tumor predisposition Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1753 of the DICER1 protein (p.Asp1753Asn). This variant is not present in population databases (gnomAD no frequency). 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: 477251). 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 with a negative predictive value of 80%. 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. -
Uncertain significance, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	Aug 22, 2023	The NM_177438.2:c.5257G>A variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 1753 (p.Asp1753Asn). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.431; 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). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; GTR ID: 500031, 61756). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4, PM1_Supporting, BS2_Supporting. (Bayesian Points: 0; VCEP specifications version 1.2.0; 08/22/23) -

Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 14, 2023

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2023

The p.D1753N variant (also known as c.5257G>A), located in coding exon 23 of the DICER1 gene, results from a G to A substitution at nucleotide position 5257. The aspartic acid at codon 1753 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly 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	Uncertain	0.47
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T;T;T;T;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;.;D;.;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D
MetaSVM	Uncertain	0.054	D
MutationAssessor	Benign	0.76	N;N;N;N;.;N
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.1	N;N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.41	T;T;T;T;T;T
Sift4G	Benign	0.71	T;T;T;T;T;T
Polyphen		1.0	D;D;D;D;.;.
Vest4		0.68
MVP		0.81
MPC		1.3
ClinPred		0.85	D
GERP RS		5.3
Varity_R		0.32
gMVP		0.67

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: rs1460430963; hg19: chr14-95560332;