rs6062302

Variant names:

• chr20-63689615-T-C
• rs6062302
• NM_001283009.2:c.1992T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 0.0150
• Publications: 47 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 403398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.1992T>C	p.Asp664Asp	synonymous_variant	Exon 23 of 35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11	c.1992T>C	p.Asp664Asp	synonymous_variant	Exon 23 of 35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7	c.2064T>C	p.Asp688Asp	synonymous_variant	Exon 23 of 35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7	c.1992T>C	p.Asp664Asp	synonymous_variant	Exon 23 of 35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6	n.2076T>C		non_coding_transcript_exon_variant	Exon 21 of 35	5		ENSP00000457428.1

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

GnomAD2 exomes AF: 0.742 AC: 184408 AN: 248428 AF XY: 0.743

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 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

African (AFR) AF: 0.950 AC: 31792 AN: 33476

American (AMR) AF: 0.736 AC: 32860 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.759 AC: 19805 AN: 26098

East Asian (EAS) AF: 0.313 AC: 12392 AN: 39650

South Asian (SAS) AF: 0.733 AC: 63217 AN: 86204

European-Finnish (FIN) AF: 0.803 AC: 41836 AN: 52068

Middle Eastern (MID) AF: 0.780 AC: 4492 AN: 5758

European-Non Finnish (NFE) AF: 0.766 AC: 851315 AN: 1111368

Other (OTH) AF: 0.748 AC: 45122 AN: 60316

GnomAD4 genome AF: 0.804 AC: 122308 AN: 152134 Hom.: 50335 Cov.: 32 AF XY: 0.800 AC XY: 59499 AN XY: 74354

African (AFR) AF: 0.938 AC: 38948 AN: 41526

American (AMR) AF: 0.772 AC: 11809 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.756 AC: 2624 AN: 3470

East Asian (EAS) AF: 0.299 AC: 1543 AN: 5156

South Asian (SAS) AF: 0.725 AC: 3498 AN: 4822

European-Finnish (FIN) AF: 0.800 AC: 8475 AN: 10600

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.776 AC: 52762 AN: 67954

Other (OTH) AF: 0.794 AC: 1672 AN: 2106

Alfa AF: 0.790 Hom.: 86394

Bravo AF: 0.804

Asia WGS AF: 0.551 AC: 1919 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Jan 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30462709) -

Jul 10, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:4

Mar 21, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dyskeratosis congenita, autosomal recessive 5 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dyskeratosis congenita Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.66
DANN	Benign	0.84
PhyloP100		0.015
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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