20-63693247-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001283009.2(RTEL1):c.2956C>T(p.Arg986Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,611,858 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000086 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000049 ( 0 hom. )
Consequence
RTEL1
NM_001283009.2 stop_gained
NM_001283009.2 stop_gained
Scores
2
5
Clinical Significance
Conservation
PhyloP100: -0.0600
Genes affected
RTEL1 (HGNC:15888): (regulator of telomere elongation helicase 1) This gene encodes a DNA helicase which functions in the stability, protection and elongation of telomeres and interacts with proteins in the shelterin complex known to protect telomeres during DNA replication. Mutations in this gene have been associated with dyskeratosis congenita and Hoyerall-Hreidarsson syndrome. Read-through transcription of this gene into the neighboring downstream gene, which encodes tumor necrosis factor receptor superfamily, member 6b, generates a non-coding transcript. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2013]
RTEL1-TNFRSF6B (HGNC:44095): (RTEL1-TNFRSF6B readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring RTEL1 (regulator of telomere elongation helicase 1) and TNFRSF6B (tumor necrosis factor receptor superfamily, member 6b, decoy) genes on chromosome 20. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is unlikely to produce a protein product. [provided by RefSeq, Feb 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 20-63693247-C-T is Pathogenic according to our data. Variant chr20-63693247-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63693247-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RTEL1 | NM_001283009.2 | c.2956C>T | p.Arg986Ter | stop_gained | 30/35 | ENST00000360203.11 | NP_001269938.1 | |
| RTEL1-TNFRSF6B | NR_037882.1 | n.3783C>T | non_coding_transcript_exon_variant | 30/38 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RTEL1 | ENST00000360203.11 | c.2956C>T | p.Arg986Ter | stop_gained | 30/35 | 5 | NM_001283009.2 | ENSP00000353332 | A2 |
Frequencies
GnomAD3 genomes 0.0000855 AC: 13AN: 152046Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000724 AC: 18AN: 248590Hom.: 0 AF XY: 0.0000592 AC XY: 8AN XY: 135028
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GnomAD4 exome AF: 0.0000486 AC: 71AN: 1459812Hom.: 0 Cov.: 33 AF XY: 0.0000399 AC XY: 29AN XY: 726214
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GnomAD4 genome 0.0000855 AC: 13AN: 152046Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5AN XY: 74256
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:7
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 23, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | RTEL1: PVS1, PS4:Moderate - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 03, 2024 | PP1, PS4, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 29, 2023 | 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; Also known as R986X; This variant is associated with the following publications: (PMID: 25607374, 27128385, 29146883, 28099038, 25940403, 25244922, 29344583, 28495916, 28930861, 30523160, 28104920, 31785789, 23329068) - |
Dyskeratosis congenita, autosomal recessive 5 Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 21, 2020 | A heterozygous nonsense variant was identified, NM_016434.3(RTEL1):c.2956C>T in exon 30 of 35 of the RTEL1 gene. This nonsense variant is predicted to create a change of an arginine to a stop at amino acid position 986 of the protein; NP_057518.1(RTEL1):p.(Arg986*), resulting in the loss of normal protein function through nonsense-mediated decay (NMD). The variant is present in the gnomAD population database at a global population frequency of 0.008% (22 heterozygotes; 0 homozygotes) with a European (Finnish) sub-population frequency of 0.03%. The variant has been previously reported in patients with RTEL1-related disorders, and has been shown to have incomplete penetrance and variable expressivity (ClinVar, Ballew, B. et al. (2013), Moriya, K. et al. (2016), Cardoso, S. et al. (2017), Petrovski, S. et al. (2017), Petersen, B. et al. (2017), Marsh, J. et al. (2018)). In addition, studies have shown that individuals with this variant have shortened telomeres (Ballew, B. et al. (2013), Cardoso, S. et al. (2017)). Other variants predicted to cause NMD have also been reported as pathogenic (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 25, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Arg986*) in the RTEL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RTEL1 are known to be pathogenic (PMID: 23453664, 23959892, 25607374). This variant is present in population databases (rs373740199, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with shortened telomeres and Hoyeraal-Hreidarsson syndrome, shortened telomeres and early onset ulcerative colitis, or idiopathic pulmonary fibrosis (PMID: 23329068, 27128385, 28099038, 28930861). This variant is also known as c.3028C>T, p.Arg1010*, and R1010X. ClinVar contains an entry for this variant (Variation ID: 65417). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 04, 2022 | - - |
Dyskeratosis congenita Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 22, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 16, 2016 | Variant summary: The RTEL1 c.3028C>T (p.Arg1010X) variant results in a premature termination codon, predicted to cause a truncated or absent RTEL1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A protein truncation would result in the loss of the PCNA (proliferating cell nuclear antigen) interacting protein (PIP) motif. This variant was found in 10/119716 control chromosomes at a frequency of 0.0000835, which does not exceed the estimated maximal expected allele frequency of a pathogenic RTEL1 variant (0.001118). The variant has been reported in three patients with Dyskeratosis congenital, two were siblings from a family who had this maternally transmitted variant in heterozygous state (other mutation was not identified by WES, but MLPA was not carried out) and another was compound heterozygous with p.Ile449Thr. Additionally, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as Likely Pathogenic. - |
Pulmonary fibrosis Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center | Jun 09, 2022 | Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted - |
RTEL1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 23, 2024 | The RTEL1 c.3028C>T variant is predicted to result in premature protein termination (p.Arg1010*). In the literature, this variant is also reported as p.986*, using a different transcript (NM_001283009.1). This variant has been reported in two siblings with dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome and was also reported in their unaffected mother (Ballew et al. 2013. PubMed ID: 23329068). This variant has also been reported in a family with interstitial lung disease, bone marrow failure, and ulcerative colitis (Borie et al. 2019. PubMed ID: 30523160; Marsh et al. 2018. PubMed ID: 29344583; Petersen et al. 2017. PubMed ID: 28930861). In one report, patients with the c.3028C>T variant also had shorted telomere lengths consistent with disease (Marsh et al. 2018. PubMed ID: 29344583). This variant is reported in 0.032% of alleles in individuals of European (Finnish) descent in gnomAD and is interpreted as pathogenic/likely pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/65417/). Nonsense variants in RTEL1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Dyskeratosis congenita, autosomal dominant 4 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2013 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A;A;A;A
Vest4
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at