rs1060503639

Variant names:

• chr14-95095882-T-C
• rs1060503639
• NM_177438.3:c.5038A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-95095882-T-C
• chr14-95095882-T-G

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.5038A>G (p.Lys1680Glu) variant in DICER1 is a missense variant predicted to cause substitution of lysine by glutamic acid at amino acid 1680 (p.Lys1680Glu). The total allele frequency in gnomAD v4.1.0 is 0.000003420 (5/1461878 alleles) with highest population minor allele frequencies of 0.00004967 (3/60396 alleles) and 0.000001799 (2/1111996) in a population of undescribed ancestry and the European (non-Finnish) population, respectively (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.697, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab data). 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: BS2_Supporting. (Bayesian Points: -1; VCEP specifications version 1.3.0; 02/27/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA16614163/MONDO:0100216/024

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:6 O:1
• Conservation: PhyloP100: 7.58
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• DICER1-related tumor predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pleuropulmonary blastoma

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• DICER1 syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received -1 ACMG points.

• BS2: 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.5038A>G	p.Lys1680Glu	missense_variant	Exon 23 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.5038A>G	p.Lys1680Glu	missense_variant	Exon 23 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251356 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111996

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000487 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

DICER1-related tumor predisposition Uncertain:2

Jan 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1680 of the DICER1 protein (p.Lys1680Glu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with unspecified cancer (PMID: 28873162). ClinVar contains an entry for this variant (Variation ID: 412143). 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 expected to disrupt DICER1 protein function with a positive 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. -

Feb 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

The NM_177438.2:c.5038A>G (p.Lys1680Glu) variant in DICER1 is a missense variant predicted to cause substitution of lysine by glutamic acid at amino acid 1680 (p.Lys1680Glu). The total allele frequency in gnomAD v4.1.0 is 0.000003420 (5/1461878 alleles) with highest population minor allele frequencies of 0.00004967 (3/60396 alleles) and 0.000001799 (2/1111996) in a population of undescribed ancestry and the European (non-Finnish) population, respectively (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.697, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab data). 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: BS2_Supporting. (Bayesian Points: -1; VCEP specifications version 1.3.0; 02/27/2024) -

Hereditary cancer-predisposing syndrome Uncertain:2

Sep 25, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K1680E variant (also known as c.5038A>G), located in coding exon 22 of the DICER1 gene, results from an A to G substitution at nucleotide position 5038. The lysine at codon 1680 is replaced by glutamic acid, an amino acid with similar 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. -

not specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Nov 10, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in at least one individual with advanced cancer undergoing multigene hereditary cancer panel testing (PMID: 28873162); This variant is associated with the following publications: (PMID: 28873162) -

Pleuropulmonary blastoma Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 09-01-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D;D;D;.;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;.;D;.;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.6	L;L;L;L;.;L
PhyloP100		7.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.3	N;N;N;N;D;N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.020	D;D;D;D;D;D
Sift4G	Uncertain	0.027	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;.;.
Vest4		0.88
MutPred		0.50		Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);.;Loss of MoRF binding (P = 0.0075);
MVP		0.97
MPC		2.8
ClinPred		0.84	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.87
Mutation Taster		=32/68	disease causing

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

Other links and lift over

dbSNP: rs1060503639; hg19: chr14-95562219;