rs776744306
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_001283009.2(RTEL1):c.2413+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001283009.2 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RTEL1 | ENST00000360203.11 | c.2413+1G>A | splice_donor_variant, intron_variant | Intron 26 of 34 | 5 | NM_001283009.2 | ENSP00000353332.5 | |||
RTEL1 | ENST00000508582.7 | c.2485+1G>A | splice_donor_variant, intron_variant | Intron 26 of 34 | 2 | ENSP00000424307.2 | ||||
RTEL1 | ENST00000370018.7 | c.2413+1G>A | splice_donor_variant, intron_variant | Intron 26 of 34 | 1 | ENSP00000359035.3 | ||||
RTEL1-TNFRSF6B | ENST00000492259.6 | n.*15+1G>A | splice_donor_variant, intron_variant | Intron 23 of 34 | 5 | ENSP00000457428.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000446 AC: 1AN: 224164Hom.: 0 AF XY: 0.00000817 AC XY: 1AN XY: 122426
GnomAD4 exome AF: 7.00e-7 AC: 1AN: 1428636Hom.: 0 Cov.: 51 AF XY: 0.00000141 AC XY: 1AN XY: 706720
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Dyskeratosis congenita, autosomal recessive 5 Pathogenic:1
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Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Pathogenic:1
This sequence change affects a donor splice site in intron 26 of the RTEL1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RTEL1 are known to be pathogenic (PMID: 23453664, 23959892, 25607374). This variant is present in population databases (rs776744306, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with familial interstitial pneumonia (PMID: 25607374). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at