chr14-95099895-C-G
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The ENST00000343455.8(DICER1):āc.4091G>Cā(p.Gly1364Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1364E) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000343455.8 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.4091G>C | p.Gly1364Ala | missense_variant | 22/27 | ENST00000343455.8 | NP_803187.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.4091G>C | p.Gly1364Ala | missense_variant | 22/27 | 1 | NM_177438.3 | ENSP00000343745 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152040Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251372Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135846
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461810Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4AN XY: 727202
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152040Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74268
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 24, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 06, 2022 | The p.G1364A variant (also known as c.4091G>C), located in coding exon 21 of the DICER1 gene, results from a G to C substitution at nucleotide position 4091. The glycine at codon 1364 is replaced by alanine, an amino acid with similar properties. In one study, this alteration was was observed in 2 individuals: a woman in her 30s with thyroid cancer and a man in his 40s with seminoma (Mirshahi UL et al. JAMA Netw Open, 2021 Feb;4:e210112). 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 22, 2024 | - - |
DICER1-related tumor predisposition Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 12, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1364 of the DICER1 protein (p.Gly1364Ala). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of DICER1-related conditions (PMID: 33630087). ClinVar contains an entry for this variant (Variation ID: 477180). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at