14-95113100-A-G

Position:

• chr14-95113100-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_177438.3(DICER1):​c.2032T>C​(p.Ser678Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. S678F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.16

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DICER1. . Gene score misZ 4.2261 (greater than the threshold 3.09). Trascript score misZ 6.1353 (greater than threshold 3.09). GenCC has associacion of gene with goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome, DICER1-related tumor predisposition, DICER1 syndrome, pleuropulmonary blastoma.
• BP4: Computational evidence support a benign effect (MetaRNN=0.082927555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.2032T>C	p.Ser678Pro	missense_variant	12/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.2032T>C	p.Ser678Pro	missense_variant	12/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

DICER1-related tumor predisposition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 18, 2021

This variant has not been reported in the literature in individuals with DICER1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with proline at codon 678 of the DICER1 protein (p.Ser678Pro). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and proline. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.18	T;T;T;T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.80	.;.;T;.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.083	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.9	N;N;N;N;N
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.17	N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.46	T;T;T;T;T
Sift4G	Benign	0.38	T;T;T;T;T
Polyphen		0.0	B;B;B;B;.
Vest4		0.12
MutPred		0.62		Loss of phosphorylation at S678 (P = 0.0435);Loss of phosphorylation at S678 (P = 0.0435);Loss of phosphorylation at S678 (P = 0.0435);Loss of phosphorylation at S678 (P = 0.0435);Loss of phosphorylation at S678 (P = 0.0435);
MVP		0.44
MPC		0.62
ClinPred		0.66	D
GERP RS		3.7
Varity_R		0.34
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-95579437;