20-63659405-G-GCCCAAGATAGTCCTGAATGGTGTGACCGTAGACTTCCCTTTCC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_001283009.2(RTEL1):​c.4_46dupCCCAAGATAGTCCTGAATGGTGTGACCGTAGACTTCCCTTTCC​(p.Gln16fs) 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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.15
Variant links:
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 Likely_pathogenic. Variant got 8 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 10 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 Protein UniProt
RTEL1NM_001283009.2 linkc.4_46dupCCCAAGATAGTCCTGAATGGTGTGACCGTAGACTTCCCTTTCC p.Gln16fs frameshift_variant 2/35 ENST00000360203.11 NP_001269938.1 Q9NZ71-6R4IXY3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RTEL1ENST00000360203.11 linkc.4_46dupCCCAAGATAGTCCTGAATGGTGTGACCGTAGACTTCCCTTTCC p.Gln16fs frameshift_variant 2/355 NM_001283009.2 ENSP00000353332.5 Q9NZ71-6
RTEL1ENST00000508582.7 linkc.4_46dupCCCAAGATAGTCCTGAATGGTGTGACCGTAGACTTCCCTTTCC p.Gln16fs frameshift_variant 2/352 ENSP00000424307.2 Q9NZ71-7
RTEL1ENST00000370018.7 linkc.4_46dupCCCAAGATAGTCCTGAATGGTGTGACCGTAGACTTCCCTTTCC p.Gln16fs frameshift_variant 2/351 ENSP00000359035.3 Q9NZ71-1
RTEL1-TNFRSF6BENST00000492259.6 linkn.4_46dupCCCAAGATAGTCCTGAATGGTGTGACCGTAGACTTCCCTTTCC non_coding_transcript_exon_variant 1/355 ENSP00000457428.1 D6RA96

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 02, 2021For 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-62290758; API