rs6062302

chr20-63689615-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001283009.2(RTEL1):c.1992T>C(p.Asp664=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.0150

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:):

ACMG classification

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	UniProt
RTEL1	NM_001283009.2	c.1992T>C	p.Asp664=	synonymous_variant	23/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1	n.2819T>C		non_coding_transcript_exon_variant	23/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.1992T>C	p.Asp664=	synonymous_variant	23/35	5	NM_001283009.2	A2

Frequencies

GnomAD3 genomes AF: 0.804 AC: 122186 AN: 152016 Hom.: 50274 Cov.: 32

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

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.: 52 AF XY: 0.755 AC XY: 548568 AN XY: 726102

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.: 32 AF XY: 0.800 AC XY: 59499 AN XY: 74354

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:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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	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:2 Other:1

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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2019	This variant is associated with the following publications: (PMID: 30462709) -
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. -

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	-0.71
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

Other links and lift over

dbSNP: rs6062302; hg19: chr20-62320968; COSMIC: COSV58894606; COSMIC: COSV58894606;