rs143099538
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2
The NM_177438.3(DICER1):โc.1583T>Cโ(p.Ile528Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (โ โ ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I528V) has been classified as Uncertain significance.
Frequency
Consequence
NM_177438.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.1583T>C | p.Ile528Thr | missense_variant | 10/27 | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.1583T>C | p.Ile528Thr | missense_variant | 10/27 | 1 | NM_177438.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251412Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135872
GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461794Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727192
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74344
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 17, 2019 | The DICER1 c.1583T>C; p.Ile528Thr variant (rs143099538) is reported in the germline of an individual with lymphoid neoplasm diffuse large B-cell lymphoma and an individual with head and neck squamous cell carcinoma (Kim 2019). This variant is reported as uncertain in ClinVar (Variation ID: 242046). It is found in the general population with an overall allele frequency of 0.002% (6/282800 alleles) in the Genome Aggregation Database. The isoleucine at codon 528 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Kim J et al. The prevalence of germline DICER1 pathogenic variation in cancer populations. Mol Genet Genomic Med. 2019 Jan 22:e555. - |
DICER1-related tumor predisposition Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 528 of the DICER1 protein (p.Ile528Thr). This variant is present in population databases (rs143099538, gnomAD 0.005%). This missense change has been observed in individual(s) with lymphoid neoplasm diffuse large Bโรรชcell lymphoma and an individual with head and neck squamous cell carcinoma (PMID: 30672147). ClinVar contains an entry for this variant (Variation ID: 242046). 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 with a negative predictive value of 80%. 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 | Nov 18, 2022 | The p.I528T variant (also known as c.1583T>C), located in coding exon 9 of the DICER1 gene, results from a T to C substitution at nucleotide position 1583. The isoleucine at codon 528 is replaced by threonine, an amino acid with similar properties. In a study of DICER1 variants in 9173 exomes from The Cancer Genome Atlas and 175 exomes from the Therapeutically Applicable Research to Generate Effective Treatment, this variant was reported in two cases (Kim J et al. Mol Genet Genomic Med, 2019 03;7:e555). And, in a cohort of 300 deceased patients, who underwent whole genome sequencing for 60 autosomal dominant cancer predisposition genes, this variant was detected and classified as a variant of uncertain significance by the authors. However, the specific phenotype of the patient(s) with this alteration was not reported (He KY et al. PLoS One, 2016 Dec;11:e0167847). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at