rs587778227

chr14-95133403-G-A

Variant summary

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

The NM_177438.3(DICER1):c.56C>T(p.Pro19Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P19S) 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 O:1
• Conservation: PhyloP100: 9.47

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.

• PP2: Missense variant where missense usually causes diseases, DICER1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.56C>T	p.Pro19Leu	missense_variant	2/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.56C>T	p.Pro19Leu	missense_variant	2/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248882 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134738

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461768 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727182

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: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

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

Mar 21, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with DICER1-related conditions. ClinVar contains an entry for this variant (Variation ID: 133963). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 19 of the DICER1 protein (p.Pro19Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 13, 2022

The p.P19L variant (also known as c.56C>T), located in coding exon 1 of the DICER1 gene, results from a C to T substitution at nucleotide position 56. The proline at codon 19 is replaced by leucine, an amino acid with similar properties. This variant was identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS One, 2014 Apr;9:e94554). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;T;T;.;T;T
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.55	N;N;N;N;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.95	N;N;N;N;N;N;N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;.
Polyphen		1.0	D;D;D;D;.;.;.
Vest4		0.68
MutPred		0.40		Loss of disorder (P = 0.0146);Loss of disorder (P = 0.0146);Loss of disorder (P = 0.0146);Loss of disorder (P = 0.0146);Loss of disorder (P = 0.0146);Loss of disorder (P = 0.0146);Loss of disorder (P = 0.0146);
MVP		0.79
MPC		1.4
ClinPred		0.70	D
GERP RS		5.6
Varity_R		0.37
gMVP		0.58

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: rs587778227; hg19: chr14-95599740;