20-63689563-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_001283009.2(RTEL1):c.1940C>T(p.Pro647Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,459,598 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. P647P) has been classified as Likely benign.
Frequency
Consequence
NM_001283009.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RTEL1 | NM_001283009.2 | c.1940C>T | p.Pro647Leu | missense_variant | 23/35 | ENST00000360203.11 | |
RTEL1-TNFRSF6B | NR_037882.1 | n.2767C>T | non_coding_transcript_exon_variant | 23/38 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RTEL1 | ENST00000360203.11 | c.1940C>T | p.Pro647Leu | missense_variant | 23/35 | 5 | NM_001283009.2 | A2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000405 AC: 1AN: 246986Hom.: 0 AF XY: 0.00000746 AC XY: 1AN XY: 134050
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1459598Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 726000
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Pulmonary fibrosis Pathogenic:1
Likely risk allele, no assertion criteria provided | research | Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center | Jun 09, 2022 | Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted - |
Dyskeratosis congenita, autosomal recessive 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 01, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 10, 2023 | Identified via exome sequencing in an individual with familial pulmonary fibrosis and shortened telomeres (Stuart et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.1940C>T (p.Pro647Leu); This variant is associated with the following publications: (PMID: 28192371, 27540018, 35795226, 25848748) - |
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 | Oct 20, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 647 of the RTEL1 protein (p.Pro647Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with a personal and family history of pulmonary fibrosis (PMID: 25848748). ClinVar contains an entry for this variant (Variation ID: 553611). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. - |
Dyskeratosis congenita Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 12, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at