chr20-63695619-G-A
Variant names:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4
The NM_001283009.2(RTEL1):c.3791G>A(p.Arg1264His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000782 in 1,611,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000079 ( 0 hom. )
Consequence
RTEL1
NM_001283009.2 missense
NM_001283009.2 missense
Scores
2
6
7
Clinical Significance
Conservation
PhyloP100: 1.50
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 7 ACMG points.
PP5
Variant 20-63695619-G-A is Pathogenic according to our data. Variant chr20-63695619-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63695619-G-A is described in Lovd as [Pathogenic]. Variant chr20-63695619-G-A is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.08357221). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RTEL1 | ENST00000360203.11 | c.3791G>A | p.Arg1264His | missense_variant | Exon 34 of 35 | 5 | NM_001283009.2 | ENSP00000353332.5 | ||
| RTEL1 | ENST00000508582.7 | c.3724+139G>A | intron_variant | Intron 34 of 34 | 2 | ENSP00000424307.2 | ||||
| RTEL1 | ENST00000370018.7 | c.3652+139G>A | intron_variant | Intron 34 of 34 | 1 | ENSP00000359035.3 | ||||
| RTEL1-TNFRSF6B | ENST00000492259.6 | n.*1254+139G>A | intron_variant | Intron 31 of 34 | 5 | ENSP00000457428.1 |
Frequencies
GnomAD3 genomes 0.0000723 AC: 11AN: 152204Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000158 AC: 39AN: 247320Hom.: 0 AF XY: 0.000178 AC XY: 24AN XY: 134780
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GnomAD4 exome AF: 0.0000788 AC: 115AN: 1459298Hom.: 0 Cov.: 34 AF XY: 0.0000813 AC XY: 59AN XY: 726002
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GnomAD4 genome 0.0000723 AC: 11AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74354
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:16Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Dyskeratosis congenita, autosomal recessive 5 Pathogenic:3Other:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 15, 2015 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 23, 2023 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 03, 2016 | - - |
not provided Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 23, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 24, 2023 | Published functional studies demonstrate a significant increase in telomere loss and increase in cells with telomere dysfunction-induced foci (Sarek et al., 2015); Observed in the heterozygous state in individuals reported to be clinically unaffected, as well as individuals with a history of pulmonary fibrosis or myelodysplastic syndrome in individuals referred for genetic testing at GeneDx and in published literature (Ballew et al., 2013; Walne et al., 2013; Cogan et al., 2015; Hanna et al., 2015); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 30088779, 23453664, 25047097, 24009516, 25607374, 26025130, 28507545, 27415407, 32135276, 32710398, 34021146, 32561545, 28104920, 25099625, 34308104, 25620558) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Mar 22, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 07, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 12, 2025 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1264 of the RTEL1 protein (p.Arg1264His). This variant is present in population databases (rs201540674, gnomAD 0.3%). This missense change has been observed in individuals with RTEL1-related conditions (PMID: 23453664, 24009516, 25047097, 25099625, 26025130). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 23453664, 24009516, 25047097, 25099625, 26025130). This variant is also known as c.3724+139G>A on transcript NM_032957.4. ClinVar contains an entry for this variant (Variation ID: 42018). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RTEL1 function (PMID: 24009516, 25620558). For these reasons, this variant has been classified as Pathogenic. - |
Dyskeratosis congenita Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 03, 2019 | The p.Arg1264His variant in RTEL1 has been reported in the homozygous state in 4 individuals with Dyskeratosis Congenita (DC) or Hoyeraal Hreidarsson (HH), a severe form of DC (Ballwe 2013, Gueye 2014, Hanna 2015). It has also been identified in the compound heterozygous state with another missense variant in an individual with HH (Walne 2013). In addition, this variant was identified in the heterozygous state in 2 siblings with pulmonary fibrosis (Cogan 2015). Although some variants in RTEL1 have been reported to be associated with increased risk for developing pulmonary fibrosis or other isolated features of DC, additional evidence would be needed to determine if this variant confers a risk for disease in the heterozgous state. This variant has also been identified in 0.35% (36/10234) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org), and a carrier screening study identified the variant in 1% of the orthodox Ashkenazi Jewish population and 0.45% of the general Ashkenazi Jewish population (Fedick 2015). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein; however, in vitro functional studies suggest that this variant impacts protein function (Sarek 2015). In summary, although the allele frequency of this variant in the Ashkenazi Jewish population of gnomAD is higher than the expected maximum allele frequency for a pathogenic variant in RTEL1, this variant meets criteria to be classified as likely pathogenic for autosomal recessive dyskeratosis congenita. ACMG/AMP Criteria applied: PM3_Strong, PS3_Moderate, PP4, BS1. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 20, 2019 | Variant summary:RTEL1 NM_032957.4:c.3724+139G>A, also known as c.3791G>A (p.Arg1264His) in NM_001283009.1 (rs201540674), is located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. Arg1264 is highly conserved and is centrally located within the putative C4C4 Zn2+ coordination domain of the encoded protein. In silico prediction algorithms (SIFT, PolyPhen-2, and Condel) indicate that this amino acid substitution is likely to be damaging to the protein (Ballew_2013). The variant allele was found at a frequency of 0.00016 in 247320 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RTEL1 causing Dyskeratosis Congenita (Hoyeraal Hreidarsson Syndrome) (0.00016 vs 0.0011), allowing no conclusion about variant significance. c.3724+139G>A has been reported in the literature in multiple individuals affected with Dyskeratosis Congenita (Hoyeraal Hreidarsson Syndrome)(Walne_2013, Ballew_2013) including at-least one ascertained report of its homozygous presence in an individual with isolated natural killer cell deficiency (Hanna_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C (Ballew_2013). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All clinical diagnostic laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Interstitial lung disease 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | University of Washington Center for Mendelian Genomics, University of Washington | May 19, 2015 | - - |
Inborn genetic diseases Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 14, 2021 | The c.3724+139G>A alteration consists of a G to A substitution 139 nucleotides after exon 34 (coding exon 33) in the NM_032957 isoform of the RTEL1 gene. This alteration is also referred to as c.3791G>A (p.R1264H), which is located in exon 34 (coding exon 33) in the NM_001283009 isoform of the RTEL1 gene, and results from a G to A substitution at nucleotide position 3791, causing the arginine (A) at amino acid position 1264 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD) database, the RTEL1 c.3724+139G>A alteration was observed in 0.01% (41/278700) of total alleles studied, with a frequency of 0.35% (36/10234) in the Ashkenazi Jewish subpopulation. This alteration has been reported in the homozygous and compound heterozygous states in patients with Hoyeraal-Hreidarsson syndrome and/or immunodeficiency. Heterozygous carriers in these families were reportedly unaffected (Ballew, 2013; Walne, 2013; Hanna, 2015). This alteration has an estimated carrier frequency of 1% in the Ashkenazi Orthodox and 0.45% in the general Ashkenazi Jewish population (Fedick, 2015). This alteration has also been identified in the heterozygous state in two siblings with adult-onset pulmonary fibrosis (Cogan, 2015). Patient-derived cell lines demonstrated deficient function as indicated by telomere length heterogeneity, the presence of extra-chromosomal circular telomeric DNA, hypersensitivity to DNA damage and increased sister chromatid exchange (Ballew, 2013). In addition, both patient-derived cells and mutant mouse embryonic fibroblasts demonstrated compromised RTEL1-TRF2 interaction leading to accumulation of telomere circles and telomere loss (Sarek, 2015). Based on the available evidence, this alteration is classified as likely pathogenic. - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Feb 09, 2022 | ACMG categories: PS3,PM3,PP3,PP5,BP1 - |
Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 15, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MVP
ClinPred
D
GERP RS
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