14-95094126-T-C

Position:

• chr14-95094126-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The ENST00000343455.8(DICER1):​c.5126A>G​(p.Asp1709Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1709N) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DICER1 ENST00000343455.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.61

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in ENST00000343455.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-95094127-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 690480.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 14-95094126-T-C is Pathogenic according to our data. Variant chr14-95094126-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 477242.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2}. Variant chr14-95094126-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DICER1	NM_177438.3	c.5126A>G	p.Asp1709Gly	missense_variant	24/27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.5126A>G	p.Asp1709Gly	missense_variant	24/27	1	NM_177438.3	ENSP00000343745	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

DICER1-related tumor predisposition Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 20, 2023	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. This variant disrupts the p.Asp1709 amino acid residue in DICER1, a functionally conserved metal-binding residue within the RNase IIIb domain (PMID: 22187960, 26408257, 23132766). Other variants that disrupt this residue have been reported in individuals with DICER1-related conditions (PMID: 22187960, 26475046, 24839956, 24676357). This suggests that this residue is clinically significant, and that variants that disrupt this residue may be disease-causing. 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 expected to disrupt DICER1 protein function. ClinVar contains an entry for this variant (Variation ID: 477242). This variant has been reported as mosaic in an individual with pleuropulmonary blastoma (PMID: 26925222). This variant also has been reported as a somatic variant in DICER1-related tumors (PMID: 22187960, 26555935, 27459524). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1709 of the DICER1 protein (p.Asp1709Gly). -
Pathogenic, criteria provided, single submitter	curation	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Jul 01, 2019	ACMG criteria met: PS2, PS3, PM1, PM2, PP4 -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2019

The p.D1709G variant (also known as c.5126A>G), located in coding exon 23 of the DICER1 gene, results from an A to G substitution at nucleotide position 5126. The aspartic acid at codon 1709 is replaced by glycine, an amino acid with similar properties. In a study of 124 children with pleuropulmonary blastoma, this variant was reported as a germline mosaic finding in one patient, who had small intestinal polyps, pleuropulmonary blastoma, and cystic nephroma (Brenneman M et al. F1000Res. 2015 Jul;4:214). This variant has been reported as a somatic finding in many studies, including studies of ovarian sex cord stromal tumors and multinodular goiters (de Kock L et al. Hum. Mutat. 2019 11;40:1939-1953). This alteration is located in the RNase IIIb domain of the DICER1 protein and variants at this codon have been characterized as somatic hotspot mutations (Foulkes WD et al. Nat. Rev. Cancer. 2014 Oct;14:662-72). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;.;D;.;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.0	H;H;H;H;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.8	D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;.;.
Vest4		0.97
MutPred		0.73		Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);.;Gain of helix (P = 0.2059);
MVP		0.98
MPC		2.7
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		0.97

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: rs1555366979; hg19: chr14-95560463; COSMIC: COSV58615493; COSMIC: COSV58615493;