rs6062302

Positions:

chr20-63689615-T-C

Variant summary

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

The NM_001283009.2(RTEL1):c.1992T>C(p.Asp664Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.76 in 1,611,728 control chromosomes in the GnomAD database, including 472,506 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 50335 hom., cov: 32)

Exomes 𝑓: 0.76 ( 422171 hom. )

Consequence

RTEL1
NM_001283009.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 0.0150

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:

RTEL1-TNFRSF6B (HGNC:):

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=-0.71).

BP6

Variant 20-63689615-T-C is Benign according to our data. Variant chr20-63689615-T-C is described in ClinVar as [Benign]. Clinvar id is 403398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63689615-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.015 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.93 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTEL1	NM_001283009.2 linkuse as main transcript	c.1992T>C	p.Asp664Asp	synonymous_variant	23/35	ENST00000360203.11	NP_001269938.1	Q9NZ71-6R4IXY3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RTEL1	ENST00000360203.11 linkuse as main transcript	c.1992T>C	p.Asp664Asp	synonymous_variant	23/35	5	NM_001283009.2	ENSP00000353332.5	Q9NZ71-6
RTEL1	ENST00000508582.7 linkuse as main transcript	c.2064T>C	p.Asp688Asp	synonymous_variant	23/35	2		ENSP00000424307.2	Q9NZ71-7
RTEL1	ENST00000370018.7 linkuse as main transcript	c.1992T>C	p.Asp664Asp	synonymous_variant	23/35	1		ENSP00000359035.3	Q9NZ71-1
RTEL1-TNFRSF6B	ENST00000492259.6 linkuse as main transcript	n.2076T>C		non_coding_transcript_exon_variant	21/35	5		ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes

AF:

0.804

AC:

122186

AN:

152016

Hom.:

50274

Cov.:

show subpopulations

Gnomad AFR

AF:

0.938

Gnomad AMI

AF:

0.814

Gnomad AMR

AF:

0.772

Gnomad ASJ

AF:

0.756

Gnomad EAS

AF:

0.299

Gnomad SAS

AF:

0.725

Gnomad FIN

AF:

0.800

Gnomad MID

AF:

0.785

Gnomad NFE

AF:

0.776

Gnomad OTH

AF:

0.797

GnomAD3 exomes

AF:

0.742

AC:

184408

AN:

248428

Hom.:

70906

AF XY:

0.743

AC XY:

100279

AN XY:

134956

show subpopulations

Gnomad AFR exome

AF:

0.943

Gnomad AMR exome

AF:

0.737

Gnomad ASJ exome

AF:

0.757

Gnomad EAS exome

AF:

0.286

Gnomad SAS exome

AF:

0.729

Gnomad FIN exome

AF:

0.803

Gnomad NFE exome

AF:

0.780

Gnomad OTH exome

AF:

0.755

GnomAD4 exome

AF:

0.756

AC:

1102831

AN:

1459594

Hom.:

422171

Cov.:

AF XY:

0.755

AC XY:

548568

AN XY:

726102

show subpopulations

Gnomad4 AFR exome

AF:

0.950

Gnomad4 AMR exome

AF:

0.736

Gnomad4 ASJ exome

AF:

0.759

Gnomad4 EAS exome

AF:

0.313

Gnomad4 SAS exome

AF:

0.733

Gnomad4 FIN exome

AF:

0.803

Gnomad4 NFE exome

AF:

0.766

Gnomad4 OTH exome

AF:

0.748

GnomAD4 genome

AF:

0.804

AC:

122308

AN:

152134

Hom.:

50335

Cov.:

AF XY:

0.800

AC XY:

59499

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.938

Gnomad4 AMR

AF:

0.772

Gnomad4 ASJ

AF:

0.756

Gnomad4 EAS

AF:

0.299

Gnomad4 SAS

AF:

0.725

Gnomad4 FIN

AF:

0.800

Gnomad4 NFE

AF:

0.776

Gnomad4 OTH

AF:

0.794

Alfa

AF:

0.789

Hom.:

57911

Bravo

AF:

0.804

Asia WGS

AF:

0.551

AC:

1919

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2018	This "variant" is the major allele. The T allele is also present at a high allel e frequency (25%) and would therefore also be benign. http://gnomad.broadinstitu te.org/variant/20-62320968-T-C -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	GeneDx	Jan 14, 2019	This variant is associated with the following publications: (PMID: 30462709) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 10, 2017	Variant summary: The c.2064T>C (p.Asp688=) 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 0.749 89112/119034 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

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.71

CADD

Benign

0.66

DANN

Benign

0.84

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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