20-63659411-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001283009.2(RTEL1):​c.9G>C​(p.Lys3Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.80
Variant links:
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]
RTEL1-TNFRSF6B (HGNC:44095): (RTEL1-TNFRSF6B readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring RTEL1 (regulator of telomere elongation helicase 1) and TNFRSF6B (tumor necrosis factor receptor superfamily, member 6b, decoy) genes on chromosome 20. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.23729151).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RTEL1NM_001283009.2 linkc.9G>C p.Lys3Asn missense_variant Exon 2 of 35 ENST00000360203.11 NP_001269938.1 Q9NZ71-6R4IXY3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RTEL1ENST00000360203.11 linkc.9G>C p.Lys3Asn missense_variant Exon 2 of 35 5 NM_001283009.2 ENSP00000353332.5 Q9NZ71-6
RTEL1ENST00000508582.7 linkc.9G>C p.Lys3Asn missense_variant Exon 2 of 35 2 ENSP00000424307.2 Q9NZ71-7
RTEL1ENST00000370018.7 linkc.9G>C p.Lys3Asn missense_variant Exon 2 of 35 1 ENSP00000359035.3 Q9NZ71-1
RTEL1-TNFRSF6BENST00000492259.6 linkn.9G>C non_coding_transcript_exon_variant Exon 1 of 35 5 ENSP00000457428.1 D6RA96

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461462
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727066
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
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
Jul 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 3 of the RTEL1 protein (p.Lys3Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RTEL1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Benign
-0.079
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.19
T;.;.;.;.
Eigen
Benign
-0.090
Eigen_PC
Benign
-0.0084
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.80
T;T;T;T;T
M_CAP
Uncertain
0.19
D
MetaRNN
Benign
0.24
T;T;T;T;T
MetaSVM
Benign
-0.46
T
MutationAssessor
Uncertain
2.1
M;M;M;.;.
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-1.7
N;N;N;N;.
REVEL
Benign
0.15
Sift
Benign
0.23
T;T;T;T;.
Sift4G
Benign
0.26
T;T;T;T;.
Polyphen
0.049
B;P;B;.;.
Vest4
0.16
MutPred
0.30
Loss of methylation at K3 (P = 0.0036);Loss of methylation at K3 (P = 0.0036);Loss of methylation at K3 (P = 0.0036);Loss of methylation at K3 (P = 0.0036);Loss of methylation at K3 (P = 0.0036);
MVP
0.78
ClinPred
0.80
D
GERP RS
3.8
Varity_R
0.21
gMVP
0.49

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-62290764; API