rs1060503636

chr14-95106174-T-Achr14-95106174-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_177438.3(DICER1):c.2854A>T(p.Thr952Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,818 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 nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T952A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.18

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 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DICER1
• BP4: Computational evidence support a benign effect (MetaRNN=0.37913775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.2854A>T	p.Thr952Ser	missense_variant	18/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.2854A>T	p.Thr952Ser	missense_variant	18/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727218

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 19, 2022

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 952 of the DICER1 protein (p.Thr952Ser). 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: 483455). 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. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2022

The p.T952S variant (also known as c.2854A>T), located in coding exon 17 of the DICER1 gene, results from an A to T substitution at nucleotide position 2854. The threonine at codon 952 is replaced by serine, 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 tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;T;T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.38	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.39	T;T;T;T;T
Sift4G	Benign	0.67	T;T;T;T;T
Polyphen		1.0	D;D;D;D;.
Vest4		0.57
MutPred		0.44		Gain of disorder (P = 0.0649);Gain of disorder (P = 0.0649);Gain of disorder (P = 0.0649);Gain of disorder (P = 0.0649);Gain of disorder (P = 0.0649);
MVP		0.67
MPC		1.0
ClinPred		0.84	D
GERP RS		5.7
Varity_R		0.45
gMVP		0.19

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: rs1060503636; hg19: chr14-95572511;