chr20-63659405-G-GCCCAAGATAGTCCTGAATGGTGTGACCGTAGACTTCCCTTTCC
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001283009.2(RTEL1):c.4_46dup(p.Gln16ProfsTer133) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
RTEL1
NM_001283009.2 frameshift
NM_001283009.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.15
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 108 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 20-63659405-G-GCCCAAGATAGTCCTGAATGGTGTGACCGTAGACTTCCCTTTCC is Pathogenic according to our data. Variant chr20-63659405-G-GCCCAAGATAGTCCTGAATGGTGTGACCGTAGACTTCCCTTTCC is described in ClinVar as [Pathogenic]. Clinvar id is 1456365.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RTEL1 | NM_001283009.2 | c.4_46dup | p.Gln16ProfsTer133 | frameshift_variant | 2/35 | ENST00000360203.11 | |
RTEL1-TNFRSF6B | NR_037882.1 | n.831_873dup | non_coding_transcript_exon_variant | 2/38 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RTEL1 | ENST00000360203.11 | c.4_46dup | p.Gln16ProfsTer133 | frameshift_variant | 2/35 | 5 | NM_001283009.2 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 02, 2021 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with RTEL1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln16Profs*133) 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.