rs1060503600

chr14-95126623-G-C

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.860C>G(p.Ser287Cys) 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. 12/21 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. S287A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.13

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 where missense usually causes diseases, DICER1
• BP4: Computational evidence support a benign effect (MetaRNN=0.22349015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.860C>G	p.Ser287Cys	missense_variant	7/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.860C>G	p.Ser287Cys	missense_variant	7/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

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

Invitae

Nov 05, 2020

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DICER1-related disease. This sequence change replaces serine with cysteine at codon 287 of the DICER1 protein (p.Ser287Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	23
Dann	Benign	0.95
DEOGEN2	Uncertain	0.79	D;D;D;D;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.90	L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.021	D;D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D
Polyphen		0.018	B;B;B;B;.
Vest4		0.25
MutPred		0.52		Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);
MVP		0.43
MPC		0.48
ClinPred		0.63	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.31

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: rs1060503600; hg19: chr14-95592960;