rs1555899111
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PM2PP3PP5_Moderate
The NM_001283009.2(RTEL1):c.102+2T>C variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
RTEL1
NM_001283009.2 splice_donor
NM_001283009.2 splice_donor
Scores
5
1
1
Splicing: ADA: 0.9883
1
1
Clinical Significance
Conservation
PhyloP100: 6.88
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.1, offset of 32, new splice context is: cggGTgggt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
PP5
?
Variant 20-63659506-T-C is Pathogenic according to our data. Variant chr20-63659506-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 496487.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RTEL1 | NM_001283009.2 | c.102+2T>C | splice_donor_variant | ENST00000360203.11 | |||
RTEL1-TNFRSF6B | NR_037882.1 | n.929+2T>C | splice_donor_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RTEL1 | ENST00000360203.11 | c.102+2T>C | splice_donor_variant | 5 | NM_001283009.2 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Dyskeratosis congenita Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 16, 2016 | Variant summary: The RTEL1 c.102+2T>C variant involves the alteration of a conserved intronic nucleotide located at the invariant GT donor splice site of intron 2. One in silico tool predicts a damaging outcome along with 4/4 splice site tools predicting the variant to result in the loss of the canonical splice donor site at intron 2. The impact the variant is likely to have on normal splicing has not been tested by in vitro studies. The variant is absent in 119504 control chromosomes while it was reported in one patient in compound heterozygosity with another likely pathogenic RTEL1 variant c.2941C>T (p.Arg981Trp). This patient presented with global bone-marrow failure, immunodeficiency, cerebellar hypoplasia, microcephaly, intrauterine growth restriction and growth retardation which are hallmarks of DKC. One reputable database classifies it as pathogenic. Considering all evidences, this variant is classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 30
DS_DL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at