rs878855272

Variant names:

• chr14-95094145-G-A
• rs878855272
• NM_177438.3:c.5107C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-95094145-G-A
• chr14-95094145-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1_Supporting PP3

This summary comes from the ClinGen Evidence Repository: NM_177438.2(DICER1):c.5107C>T variant in DICER1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 1703 (p.Arg1703Cys). The total allele frequency in gnomAD v4.1.0 is 0.000003098 (5/1614132 alleles) with a highest population minor allele frequency of 0.00002196 (2/91074 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met). This variant resides within the RNase IIIb mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID:31342592). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.916) (PP3). 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: PM1_Supporting, PP3. (Bayesian Points: 2; VCEP specifications version 1.3.0; 08/27/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10583187/MONDO:0017288/024

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (1 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:3
• Conservation: PhyloP100: 9.52

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 2 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3	c.5107C>T	p.Arg1703Cys	missense_variant	Exon 24 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.5107C>T	p.Arg1703Cys	missense_variant	Exon 24 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461876 Hom.: 1 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727240

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

DICER1-related tumor predisposition Uncertain:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1703 of the DICER1 protein (p.Arg1703Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%), including at least one homozygous and/or hemizygous individual. 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: 242130). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DICER1 protein function. 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. -

Aug 27, 2024

ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

NM_177438.2(DICER1):c.5107C>T variant in DICER1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 1703 (p.Arg1703Cys). The total allele frequency in gnomAD v4.1.0 is 0.000003098 (5/1614132 alleles) with a highest population minor allele frequency of 0.00002196 (2/91074 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met). This variant resides within the RNase IIIb mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.916) (PP3). 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: PM1_Supporting, PP3. (Bayesian Points: 2; VCEP specifications version 1.3.0; 08/27/2024). -

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1703C variant (also known as c.5107C>T), located in coding exon 23 of the DICER1 gene, results from a C to T substitution at nucleotide position 5107. The arginine at codon 1703 is replaced by cysteine, 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. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D;D;D;.;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;.;D;.;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.0	H;H;H;H;.;H
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.7	D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;.;.
Vest4		0.87
MutPred		0.74		Gain of catalytic residue at E1705 (P = 0.1294);Gain of catalytic residue at E1705 (P = 0.1294);Gain of catalytic residue at E1705 (P = 0.1294);Gain of catalytic residue at E1705 (P = 0.1294);.;Gain of catalytic residue at E1705 (P = 0.1294);
MVP		0.98
MPC		2.7
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.95

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

Other links and lift over

dbSNP: rs878855272; hg19: chr14-95560482; COSMIC: COSV58624724; COSMIC: COSV58624724;