14-95096625-G-C

Variant names:

• chr14-95096625-G-C
• rs747593690
• NM_177438.3:c.4295C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_177438.3(DICER1):​c.4295C>G​(p.Pro1432Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,430 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the DICER1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 111 curated benign missense variants. Gene score misZ: 4.2261 (above the threshold of 3.09). Trascript score misZ: 6.1353 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3	c.4295C>G	p.Pro1432Arg	missense_variant	Exon 23 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.4295C>G	p.Pro1432Arg	missense_variant	Exon 23 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459430 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725990

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

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

Jan 14, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). 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. This sequence change replaces proline with arginine at codon 1432 of the DICER1 protein (p.Pro1432Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;T;T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	.;.;D;.;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.4	M;M;M;M;.;M
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.64	N;N;N;N;N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.012	D;D;D;D;D;D
Sift4G	Benign	0.13	T;T;T;T;T;D
Polyphen		1.0	D;D;D;D;.;.
Vest4		0.77
MutPred		0.41		Loss of catalytic residue at P1432 (P = 0.007);Loss of catalytic residue at P1432 (P = 0.007);Loss of catalytic residue at P1432 (P = 0.007);Loss of catalytic residue at P1432 (P = 0.007);.;Loss of catalytic residue at P1432 (P = 0.007);
MVP		0.88
MPC		1.4
ClinPred		0.93	D
GERP RS		5.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.14
gMVP		0.43

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: rs747593690; hg19: chr14-95562962;