NM_001283009.2:c.2274G>A

Variant names:

• chr20-63690302-G-A
• rs2236506
• NM_001283009.2:c.2274G>A

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.2274G>A​(p.Ala758Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.756 in 1,605,792 control chromosomes in the GnomAD database, including 465,069 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. A758A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.79 (47801 hom., cov: 34)
  • Exomes 𝑓: 0.75 (417268 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -2.98
• Publications: 35 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=-0.89).
• BP6: Variant 20-63690302-G-A is Benign according to our data. Variant chr20-63690302-G-A is described in ClinVar as Benign. ClinVar VariationId is 403400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.98 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.2274G>A	p.Ala758Ala	synonymous_variant	Exon 26 of 35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11	c.2274G>A	p.Ala758Ala	synonymous_variant	Exon 26 of 35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7	c.2346G>A	p.Ala782Ala	synonymous_variant	Exon 26 of 35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7	c.2274G>A	p.Ala758Ala	synonymous_variant	Exon 26 of 35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6	n.2234G>A		non_coding_transcript_exon_variant	Exon 23 of 35	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes AF: 0.785 AC: 119362 AN: 152006 Hom.: 47755 Cov.: 34

Gnomad AFR AF: 0.876

Gnomad AMI AF: 0.815

Gnomad AMR AF: 0.765

Gnomad ASJ AF: 0.749

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.724

Gnomad FIN AF: 0.800

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.776

Gnomad OTH AF: 0.783

GnomAD2 exomes AF: 0.736 AC: 182107 AN: 247270 AF XY: 0.739

Gnomad AFR exome AF: 0.880

Gnomad AMR exome AF: 0.734

Gnomad ASJ exome AF: 0.751

Gnomad EAS exome AF: 0.279

Gnomad FIN exome AF: 0.803

Gnomad NFE exome AF: 0.779

Gnomad OTH exome AF: 0.750

GnomAD4 exome AF: 0.753 AC: 1094386 AN: 1453668 Hom.: 417268 Cov.: 69 AF XY: 0.753 AC XY: 543510 AN XY: 721870

African (AFR) AF: 0.885 AC: 29548 AN: 33372

American (AMR) AF: 0.732 AC: 32511 AN: 44406

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 19547 AN: 25998

East Asian (EAS) AF: 0.303 AC: 11944 AN: 39464

South Asian (SAS) AF: 0.732 AC: 62974 AN: 85980

European-Finnish (FIN) AF: 0.804 AC: 41603 AN: 51764

Middle Eastern (MID) AF: 0.775 AC: 4453 AN: 5746

European-Non Finnish (NFE) AF: 0.765 AC: 847261 AN: 1106968

Other (OTH) AF: 0.743 AC: 44545 AN: 59970

GnomAD4 genome AF: 0.785 AC: 119466 AN: 152124 Hom.: 47801 Cov.: 34 AF XY: 0.782 AC XY: 58177 AN XY: 74374

African (AFR) AF: 0.876 AC: 36358 AN: 41514

American (AMR) AF: 0.765 AC: 11689 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.749 AC: 2599 AN: 3472

East Asian (EAS) AF: 0.291 AC: 1502 AN: 5166

South Asian (SAS) AF: 0.724 AC: 3494 AN: 4824

European-Finnish (FIN) AF: 0.800 AC: 8472 AN: 10594

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.776 AC: 52732 AN: 67956

Other (OTH) AF: 0.780 AC: 1645 AN: 2108

Alfa AF: 0.790 Hom.: 20006

Bravo AF: 0.783

Asia WGS AF: 0.544 AC: 1893 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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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. -

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 RTEL1 c.2346G>A (p.Ala782Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 88140/118930 control chromosomes (33801 homozygotes) at a frequency of 0.7411082, which is approximately 663 times the estimated maximal expected allele frequency of a pathogenic RTEL1 variant (0.001118), indicating the variant is the major allele and is benign. In addition, one clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as benign. -

not specified Benign:4

Mar 06, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The A "variant" is the major allele in the Genome Aggregation Database (gnomAD; http://gnomad.broadinstitute.org; dbSNP rs2236506). -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

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
AlphaMissense	Benign	0.10
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.73
DANN	Benign	0.84
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2236506; hg19: chr20-62321655; COSMIC: COSV58893321; COSMIC: COSV58893321;