rs138576158

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001283009.2(RTEL1):ā€‹c.3107C>Gā€‹(p.Thr1036Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000414 in 1,594,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000072 ( 0 hom., cov: 31)
Exomes š‘“: 0.000038 ( 0 hom. )

Consequence

RTEL1
NM_001283009.2 missense, splice_region

Scores

19
Splicing: ADA: 0.00003521
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.00900
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.028148651).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RTEL1NM_001283009.2 linkuse as main transcriptc.3107C>G p.Thr1036Arg missense_variant, splice_region_variant 31/35 ENST00000360203.11 NP_001269938.1 Q9NZ71-6R4IXY3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RTEL1ENST00000360203.11 linkuse as main transcriptc.3107C>G p.Thr1036Arg missense_variant, splice_region_variant 31/355 NM_001283009.2 ENSP00000353332.5 Q9NZ71-6
RTEL1ENST00000508582.7 linkuse as main transcriptc.3179C>G p.Thr1060Arg missense_variant, splice_region_variant 31/352 ENSP00000424307.2 Q9NZ71-7
RTEL1ENST00000370018.7 linkuse as main transcriptc.3107C>G p.Thr1036Arg missense_variant, splice_region_variant 31/351 ENSP00000359035.3 Q9NZ71-1
RTEL1-TNFRSF6BENST00000492259.6 linkuse as main transcriptn.*709C>G splice_region_variant, non_coding_transcript_exon_variant 28/355 ENSP00000457428.1 D6RA96
RTEL1-TNFRSF6BENST00000492259.6 linkuse as main transcriptn.*709C>G 3_prime_UTR_variant 28/355 ENSP00000457428.1 D6RA96

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152232
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00259
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000821
AC:
20
AN:
243572
Hom.:
0
AF XY:
0.0000528
AC XY:
7
AN XY:
132666
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00156
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000185
Gnomad OTH exome
AF:
0.000502
GnomAD4 exome
AF:
0.0000381
AC:
55
AN:
1441992
Hom.:
0
Cov.:
31
AF XY:
0.0000350
AC XY:
25
AN XY:
714238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00159
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000456
Gnomad4 OTH exome
AF:
0.000151
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152232
Hom.:
0
Cov.:
31
AF XY:
0.000108
AC XY:
8
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00259
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000226
Hom.:
0
Bravo
AF:
0.0000567
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000351
AC:
3
ExAC
AF:
0.0000500
AC:
6
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 13, 2024In silico analysis indicates that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge -
Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 30, 2022This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 1036 of the RTEL1 protein (p.Thr1036Arg). This variant is present in population databases (rs138576158, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with RTEL1-related conditions. This variant is also known as NM_032957.4:c.3179C>G (p.Thr1060Arg). ClinVar contains an entry for this variant (Variation ID: 572880). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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, criteria provided, single submittercurationSema4, Sema4Aug 19, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.060
BayesDel_addAF
Benign
-0.069
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
14
DANN
Benign
0.66
DEOGEN2
Benign
0.12
T;.;.;.
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.24
N
LIST_S2
Benign
0.67
T;T;T;T
M_CAP
Benign
0.083
D
MetaRNN
Benign
0.028
T;T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.1
L;.;L;.
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.53
N;N;N;.
REVEL
Benign
0.27
Sift
Benign
0.46
T;T;T;.
Sift4G
Benign
0.47
T;T;T;T
Polyphen
0.0050
B;B;B;.
Vest4
0.21
MVP
0.74
ClinPred
0.018
T
GERP RS
-1.4
Varity_R
0.045
gMVP
0.25

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000035
dbscSNV1_RF
Benign
0.014
SpliceAI score (max)
0.34
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.34
Position offset: 39

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs138576158; hg19: chr20-62325839; API