rs758615955
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_001283009.2(RTEL1):c.940G>A(p.Asp314Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000359 in 1,614,074 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 29)
Exomes 𝑓: 0.000037 ( 0 hom. )
Consequence
RTEL1
NM_001283009.2 missense
NM_001283009.2 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 4.57
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 Likely_benign. Variant got -1 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.3164496).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RTEL1 | NM_001283009.2 | c.940G>A | p.Asp314Asn | missense_variant | 11/35 | ENST00000360203.11 | |
RTEL1-TNFRSF6B | NR_037882.1 | n.1767G>A | non_coding_transcript_exon_variant | 11/38 | |||
LOC124904954 | XR_007067717.1 | n.211C>T | non_coding_transcript_exon_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RTEL1 | ENST00000360203.11 | c.940G>A | p.Asp314Asn | missense_variant | 11/35 | 5 | NM_001283009.2 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152216Hom.: 0 Cov.: 29
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251292Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135862
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GnomAD4 exome AF: 0.0000369 AC: 54AN: 1461858Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25AN XY: 727226
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152216Hom.: 0 Cov.: 29 AF XY: 0.0000403 AC XY: 3AN XY: 74350
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
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 | Sep 01, 2021 | This sequence change replaces aspartic acid with asparagine at codon 314 of the RTEL1 protein (p.Asp314Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs758615955, ExAC 0.003%). This variant has not been reported in the literature in individuals affected with RTEL1-related conditions. 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 tolerated. 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. | Nov 11, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;M;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;.
REVEL
Benign
Sift
Benign
D;D;D;.
Sift4G
Benign
T;T;T;T
Polyphen
B;P;B;.
Vest4
MVP
ClinPred
D
GERP RS
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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