14-95107753-A-G

Variant names:

• chr14-95107753-A-G
• rs878855251
• NM_177438.3:c.2659T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_177438.3(DICER1):​c.2659T>C​(p.Ser887Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000149 in 1,341,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. S887Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.73
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22271642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3	c.2659T>C	p.Ser887Pro	missense_variant	Exon 17 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.2659T>C	p.Ser887Pro	missense_variant	Exon 17 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1341498 Hom.: 0 Cov.: 39 AF XY: 0.00000149 AC XY: 1 AN XY: 670404

African (AFR) AF: 0.00 AC: 0 AN: 30892

American (AMR) AF: 0.00 AC: 0 AN: 43564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24370

East Asian (EAS) AF: 0.00 AC: 0 AN: 37294

South Asian (SAS) AF: 0.00 AC: 0 AN: 83834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5438

European-Non Finnish (NFE) AF: 0.00000198 AC: 2 AN: 1010478

Other (OTH) AF: 0.00 AC: 0 AN: 55516

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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

Jul 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 887 of the DICER1 protein (p.Ser887Pro). 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: 242068). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jul 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S887P variant (also known as c.2659T>C), located in coding exon 16 of the DICER1 gene, results from a T to C substitution at nucleotide position 2659. The serine at codon 887 is replaced by proline, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Benign	0.29
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T;T;T;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	.;.;D;.;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L;L;L;L;L
PhyloP100		5.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.2	N;N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.031	D;D;D;D;D
Sift4G	Benign	0.23	T;T;T;T;T
Polyphen		0.51	P;P;P;P;.
Vest4		0.47
MutPred		0.37		Loss of catalytic residue at S887 (P = 0.0991);Loss of catalytic residue at S887 (P = 0.0991);Loss of catalytic residue at S887 (P = 0.0991);Loss of catalytic residue at S887 (P = 0.0991);Loss of catalytic residue at S887 (P = 0.0991);
MVP		0.86
MPC		1.3
ClinPred		0.75	D
GERP RS		5.9
Varity_R		0.86
gMVP		0.80
Mutation Taster		=15/85	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: rs878855251; hg19: chr14-95574090;