rs886037684
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_177438.3(DICER1):c.2062C>T(p.Arg688Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,746 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R688R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_177438.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.2062C>T | p.Arg688Ter | stop_gained | 13/27 | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.2062C>T | p.Arg688Ter | stop_gained | 13/27 | 1 | NM_177438.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152018Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461728Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727168
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152018Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74222
ClinVar
Submissions by phenotype
DICER1-related tumor predisposition Pathogenic:4
Pathogenic, criteria provided, single submitter | curation | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Jul 01, 2019 | ACMG criteria met: PVS1, PM2, PM7, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota | Nov 10, 2014 | - - |
Pathogenic, no assertion criteria provided | research | Donald Williams Parsons Laboratory, Baylor College of Medicine | Oct 28, 2013 | This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in this study maternally inherited in a 1-year-old male with pulmonary pleuroblastoma - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change creates a premature translational stop signal (p.Arg688*) in the DICER1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DICER1 are known to be pathogenic (PMID: 19556464, 21266384). This variant is present in population databases (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of DICER1 syndrome (PMID: 26822237, 26925222, 26928971, 28323992, 28960912). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 254303). For these reasons, this variant has been classified as Pathogenic. - |
Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 26, 2024 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2021 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26925222, 26461232, 26822237, 26928971, 27697588, 28097783, 28862265, 29762508, 28960912, 28323992) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 06, 2022 | The p.R688* pathogenic mutation (also known as c.2062C>T), located in coding exon 12 of the DICER1 gene, results from a C to T substitution at nucleotide position 2062. This changes the amino acid from an arginine to a stop codon within coding exon 12. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with DICER1-related disease (Wu MK et al. Pediatr Blood Cancer, 2016 07;63:1272-5; Parsons DW et al. JAMA Oncol, 2016 May;2:616-624; Khan NE et al. J Clin Endocrinol Metab, 2017 05;102:1614-1622; Fita AM et al. Pediatr Blood Cancer, 2017 Aug;64; Brenneman M et al. F1000Res, 2015 Jul;4:214; de Kock L et al. Mod Pathol, 2020 06;33:1207-1219). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at