rs41309931

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001283009.2(RTEL1):​c.3499+5G>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,610,464 control chromosomes in the GnomAD database, including 14,426 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1207 hom., cov: 32)
Exomes 𝑓: 0.12 ( 13219 hom. )

Consequence

RTEL1
NM_001283009.2 splice_donor_5th_base, intron

Scores

2
Splicing: ADA: 0.9398
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 1.33
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 20-63695226-G-T is Benign according to our data. Variant chr20-63695226-G-T is described in ClinVar as [Benign]. Clinvar id is 403403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63695226-G-T is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RTEL1NM_001283009.2 linkuse as main transcriptc.3499+5G>T splice_donor_5th_base_variant, intron_variant ENST00000360203.11
RTEL1-TNFRSF6BNR_037882.1 linkuse as main transcriptn.4326+5G>T splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RTEL1ENST00000360203.11 linkuse as main transcriptc.3499+5G>T splice_donor_5th_base_variant, intron_variant 5 NM_001283009.2 A2Q9NZ71-6

Frequencies

GnomAD3 genomes
AF:
0.104
AC:
15817
AN:
151970
Hom.:
1202
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0282
Gnomad AMI
AF:
0.0921
Gnomad AMR
AF:
0.234
Gnomad ASJ
AF:
0.0821
Gnomad EAS
AF:
0.231
Gnomad SAS
AF:
0.107
Gnomad FIN
AF:
0.0749
Gnomad MID
AF:
0.0886
Gnomad NFE
AF:
0.116
Gnomad OTH
AF:
0.127
GnomAD3 exomes
AF:
0.149
AC:
36332
AN:
244330
Hom.:
4073
AF XY:
0.141
AC XY:
18827
AN XY:
133414
show subpopulations
Gnomad AFR exome
AF:
0.0252
Gnomad AMR exome
AF:
0.365
Gnomad ASJ exome
AF:
0.0847
Gnomad EAS exome
AF:
0.220
Gnomad SAS exome
AF:
0.109
Gnomad FIN exome
AF:
0.0814
Gnomad NFE exome
AF:
0.116
Gnomad OTH exome
AF:
0.144
GnomAD4 exome
AF:
0.124
AC:
181111
AN:
1458376
Hom.:
13219
Cov.:
35
AF XY:
0.122
AC XY:
88833
AN XY:
725286
show subpopulations
Gnomad4 AFR exome
AF:
0.0229
Gnomad4 AMR exome
AF:
0.350
Gnomad4 ASJ exome
AF:
0.0848
Gnomad4 EAS exome
AF:
0.230
Gnomad4 SAS exome
AF:
0.109
Gnomad4 FIN exome
AF:
0.0869
Gnomad4 NFE exome
AF:
0.118
Gnomad4 OTH exome
AF:
0.126
GnomAD4 genome
AF:
0.104
AC:
15838
AN:
152088
Hom.:
1207
Cov.:
32
AF XY:
0.105
AC XY:
7776
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.0281
Gnomad4 AMR
AF:
0.234
Gnomad4 ASJ
AF:
0.0821
Gnomad4 EAS
AF:
0.232
Gnomad4 SAS
AF:
0.108
Gnomad4 FIN
AF:
0.0749
Gnomad4 NFE
AF:
0.116
Gnomad4 OTH
AF:
0.132
Alfa
AF:
0.125
Hom.:
632
Bravo
AF:
0.116
Asia WGS
AF:
0.176
AC:
612
AN:
3478
EpiCase
AF:
0.120
EpiControl
AF:
0.116

ClinVar

Significance: Benign
Submissions summary: Benign:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingUnidad de Genómica Garrahan, Hospital de Pediatría GarrahanJan 24, 2024This variant is classified as Benign based on local population frequency. This variant was detected in 43% of patients studied by a panel of primary immunodeficiencies. Number of patients: 41. Only high quality variants are reported. -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 29, 2016Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
not provided Benign:1Other:1
Benign, criteria provided, single submitterclinical testingGeneDxNov 12, 2018- -
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Dyskeratosis congenita, autosomal recessive 5 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 10, 2021- -
Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 10, 2021- -
Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Dyskeratosis congenita Benign:1
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
CADD
Benign
17
DANN
Benign
0.82
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.94
dbscSNV1_RF
Benign
0.67
SpliceAI score (max)
0.17
Details are displayed if max score is > 0.2

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: rs41309931; hg19: chr20-62326579; COSMIC: COSV53926756; COSMIC: COSV53926756; API