rs747497376
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_001283009.2(RTEL1):c.1675T>A(p.Phe559Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,322 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 (★★). Synonymous variant affecting the same amino acid position (i.e. F559F) has been classified as Likely benign.
Frequency
Consequence
NM_001283009.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RTEL1 | NM_001283009.2 | c.1675T>A | p.Phe559Ile | missense_variant | 20/35 | ENST00000360203.11 | |
RTEL1-TNFRSF6B | NR_037882.1 | n.2502T>A | non_coding_transcript_exon_variant | 20/38 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RTEL1 | ENST00000360203.11 | c.1675T>A | p.Phe559Ile | missense_variant | 20/35 | 5 | NM_001283009.2 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249636Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135590
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460322Hom.: 0 Cov.: 34 AF XY: 0.00000551 AC XY: 4AN XY: 726462
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 05, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29361909) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | RTEL1: PM2:Supporting, PP3 - |
Dyskeratosis congenita, autosomal recessive 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | - - |
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 | Aug 23, 2022 | This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 559 of the RTEL1 protein (p.Phe559Ile). This variant is present in population databases (rs747497376, gnomAD 0.0009%). This missense change has been observed in individual(s) with familial interstitial pneumonia (PMID: 29361909). ClinVar contains an entry for this variant (Variation ID: 473909). 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 C15"). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at