rs1060503603

Variant names:

• chr14-95103683-A-G
• rs1060503603
• NM_177438.3:c.3713T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-95103683-A-G
• chr14-95103683-A-T

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.3713T>C​(p.Leu1238Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 2.00

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 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14673173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3	c.3713T>C	p.Leu1238Pro	missense_variant	Exon 21 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.3713T>C	p.Leu1238Pro	missense_variant	Exon 21 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome Uncertain:1

Mar 22, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Childhood kidney cell carcinoma;C5670122:High-grade astrocytoma with piloid features Uncertain:1

-

Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Uncertain:1

Nov 29, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

DICER1-related tumor predisposition Uncertain:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1238 of the DICER1 protein (p.Leu1238Pro). 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: 412075). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DICER1 protein function with a negative predictive value of 95%. 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

May 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L1238P variant (also known as c.3713T>C), located in coding exon 20 of the DICER1 gene, results from a T to C substitution at nucleotide position 3713. The leucine at codon 1238 is replaced by proline, an amino acid with similar properties. This amino acid position is not well 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	0.062
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.37	T;T;T;T;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.74	.;.;T;.;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.55	N;N;N;N;.;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.15	N;N;N;N;N;N
REVEL	Benign	0.080
Sift	Benign	0.097	T;T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;.;.
Vest4		0.48
MutPred		0.43		Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);.;Gain of loop (P = 0.0312);
MVP		0.76
MPC		0.79
ClinPred		0.047	T
GERP RS		1.9
Varity_R		0.088
gMVP		0.73

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: rs1060503603; hg19: chr14-95570020;