rs3208007

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001283009.2(RTEL1):c.2544T>C(p.Pro848=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.761 in 1,553,268 control chromosomes in the GnomAD database, including 456,312 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P848P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.80 ( 50420 hom., cov: 34)

Exomes 𝑓: 0.76 ( 405892 hom. )

Consequence

RTEL1
NM_001283009.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -2.58

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 links:

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]

RTEL1-TNFRSF6B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 20-63690935-T-C is Benign according to our data. Variant chr20-63690935-T-C is described in ClinVar as [Benign]. Clinvar id is 403401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63690935-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.58 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.931 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2 linkuse as main transcript	c.2544T>C	p.Pro848=	synonymous_variant	27/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1 linkuse as main transcript	n.3371T>C		non_coding_transcript_exon_variant	27/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11 linkuse as main transcript	c.2544T>C	p.Pro848=	synonymous_variant	27/35	5	NM_001283009.2	A2	Q9NZ71-6

Frequencies

GnomAD3 genomes

AF:

0.804

AC:

122271

AN:

152006

Hom.:

50359

Cov.:

show subpopulations

Gnomad AFR

AF:

0.938

Gnomad AMI

AF:

0.814

Gnomad AMR

AF:

0.772

Gnomad ASJ

AF:

0.768

Gnomad EAS

AF:

0.291

Gnomad SAS

AF:

0.725

Gnomad FIN

AF:

0.800

Gnomad MID

AF:

0.785

Gnomad NFE

AF:

0.777

Gnomad OTH

AF:

0.795

GnomAD3 exomes

AF:

0.739

AC:

118199

AN:

159858

Hom.:

45231

AF XY:

0.737

AC XY:

62662

AN XY:

85076

show subpopulations

Gnomad AFR exome

AF:

0.943

Gnomad AMR exome

AF:

0.741

Gnomad ASJ exome

AF:

0.769

Gnomad EAS exome

AF:

0.286

Gnomad SAS exome

AF:

0.729

Gnomad FIN exome

AF:

0.806

Gnomad NFE exome

AF:

0.779

Gnomad OTH exome

AF:

0.756

GnomAD4 exome

AF:

0.756

AC:

1059519

AN:

1401142

Hom.:

405892

Cov.:

AF XY:

0.756

AC XY:

522571

AN XY:

691670

show subpopulations

Gnomad4 AFR exome

AF:

0.950

Gnomad4 AMR exome

AF:

0.739

Gnomad4 ASJ exome

AF:

0.771

Gnomad4 EAS exome

AF:

0.307

Gnomad4 SAS exome

AF:

0.733

Gnomad4 FIN exome

AF:

0.804

Gnomad4 NFE exome

AF:

0.766

Gnomad4 OTH exome

AF:

0.749

GnomAD4 genome

AF:

0.805

AC:

122393

AN:

152126

Hom.:

50420

Cov.:

AF XY:

0.800

AC XY:

59538

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.938

Gnomad4 AMR

AF:

0.772

Gnomad4 ASJ

AF:

0.768

Gnomad4 EAS

AF:

0.292

Gnomad4 SAS

AF:

0.725

Gnomad4 FIN

AF:

0.800

Gnomad4 NFE

AF:

0.777

Gnomad4 OTH

AF:

0.792

Alfa

AF:

0.783

Hom.:

23153

Bravo

AF:

0.805

Asia WGS

AF:

0.551

AC:

1920

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant 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 -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 89% of patients studied by a panel of primary immunodeficiencies. Number of patients: 85. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2018	- -
not provided, no classification provided	phenotyping only	GenomeConnect, 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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 10, 2017	Variant summary: The c.2616T>C (p.Pro872=) in RTEL1 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this does not affect a normal splicing pattern, however no functional studies supporting these predictions were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.7653 20201/26266 chrs tested), including numerous homozygous occurrences. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0011). In addition, the variant is cited as Benign/Polymorphism by a reputable database/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

Dyskeratosis congenita, autosomal recessive 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Dyskeratosis congenita

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

Cadd

Benign

0.069

Dann

Benign

0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over