chr20-63695558-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_001283009.2(RTEL1):c.3730T>C(p.Cys1244Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,460,072 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 Uncertain significance (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
RTEL1
NM_001283009.2 missense
NM_001283009.2 missense
Scores
5
4
6
Clinical Significance
Conservation
PhyloP100: 1.26
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 Uncertain_significance. Variant got 2 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.896
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RTEL1 | NM_001283009.2 | c.3730T>C | p.Cys1244Arg | missense_variant | 34/35 | ENST00000360203.11 | |
RTEL1-TNFRSF6B | NR_037882.1 | n.4557T>C | non_coding_transcript_exon_variant | 34/38 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RTEL1 | ENST00000360203.11 | c.3730T>C | p.Cys1244Arg | missense_variant | 34/35 | 5 | NM_001283009.2 | A2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.0000202 AC: 5AN: 247318Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135024
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GnomAD4 exome AF: 0.0000171 AC: 25AN: 1460072Hom.: 0 Cov.: 34 AF XY: 0.0000179 AC XY: 13AN XY: 726358
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Dyskeratosis congenita, autosomal recessive 5 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 15, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 28, 2017 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 22, 2023 | The c.3724+78T>C intronic alteration results from a T to C substitution 78 nucleotides after coding exon 33 of the RTEL1 gene._x000D_ _x000D_ _x000D_ _x000D_ The c.3730T>C (p.C1244R) alteration is located in exon 34 (coding exon 33) of the RTEL1 gene. This alteration results from a T to C substitution at nucleotide position 3730, causing the cysteine (C) at amino acid position 1244 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of 0.002% (5/247318) total alleles studied. The highest observed frequency was 0.005% (1/18282) of East Asian alleles. This variant was detected in two affected siblings with shortened telomere length and abnormal telomere function. Both of these siblings were compound heterozygous carriers of this variant as well as RTEL1 c.2097C>G (p.I699M) (Le Guen, 2013). This variant has also been detected in heterozygous form in a 61 year old female with idiopathic pulmonary fibrosis post lung transplant who also had severely shortened telomeres (Popescu, 2019). This nucleotide position is highly conserved in available vertebrate species._x000D_ _x000D_ Leave out nucleotide conservation sentence and table? The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 01, 2017 | DNA sequence analysis of the RTEL1 gene demonstrated a sequence change, c.3730T>C, in exon 34 that results in an amino acid change, p.Cys1244Arg. The p.Cys1244Arg change affects a moderately conserved amino acid residue located in a domain of the RTEL1 protein that is known to be functional. The p.Cys1244Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). This variant is present in 5 individuals in gnomAD (0.002% frequency in the global population). This sequence change has been described in the compound heterozygous state with another variant in two siblings with Hoyeraal-Hreidarsson syndrome and not present in their unaffected sibling (Le Guen et al. 2013). Additionally, analysis of these patient's primary fibroblasts demonstrated shorter telomeres and genome instability (Le Guen et al. 2013). - |
Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 06, 2019 | This sequence change replaces cysteine with arginine at codon 1244 of the RTEL1 protein (p.Cys1244Arg). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs587777037, ExAC 0.003%). This variant has been observed to segregate with Hoyeraal–Hreidarsson syndrome in a family (PMID: 23591994). This variant has also been observed in an individual with aplastic anemia (PMID: 30995915). ClinVar contains an entry for this variant (Variation ID: 65412). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;N;N;N
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.0775);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at