rs558133631

Variant names:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_SupportingBP6_Very_StrongBS1BS2

The NM_001283009.2(RTEL1):c.2313_2315delAGA(p.Glu771del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,610,860 control chromosomes in the GnomAD database, including 30 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0053 ( 27 hom. )

Consequence

RTEL1
NM_001283009.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.71

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 -15 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001283009.2. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 20-63690337-GAGA-G is Benign according to our data. Variant chr20-63690337-GAGA-G is described in ClinVar as [Likely_benign]. Clinvar id is 436568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00483 (736/152298) while in subpopulation NFE AF= 0.00609 (414/68002). AF 95% confidence interval is 0.0056. There are 3 homozygotes in gnomad4. There are 378 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2 link	c.2313_2315delAGA	p.Glu771del	disruptive_inframe_deletion	Exon 26 of 35	ENST00000360203.11	NP_001269938.1	Q9NZ71-6R4IXY3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RTEL1	ENST00000360203.11 link	c.2313_2315delAGA	p.Glu771del	disruptive_inframe_deletion	Exon 26 of 35	5	NM_001283009.2	ENSP00000353332.5	Q9NZ71-6
RTEL1	ENST00000508582.7 link	c.2385_2387delAGA	p.Glu795del	disruptive_inframe_deletion	Exon 26 of 35	2		ENSP00000424307.2	Q9NZ71-7
RTEL1	ENST00000370018.7 link	c.2313_2315delAGA	p.Glu771del	disruptive_inframe_deletion	Exon 26 of 35	1		ENSP00000359035.3	Q9NZ71-1
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.2273_2275delAGA		non_coding_transcript_exon_variant	Exon 23 of 35	5		ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes

AF:

0.00484

AC:

737

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00582

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.0158

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00609

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00555

AC:

1379

AN:

248682

Hom.:

AF XY:

0.00538

AC XY:

726

AN XY:

135034

show subpopulations

Gnomad AFR exome

AF:

0.000748

Gnomad AMR exome

AF:

0.00407

Gnomad ASJ exome

AF:

0.00182

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00141

Gnomad FIN exome

AF:

0.0160

Gnomad NFE exome

AF:

0.00708

Gnomad OTH exome

AF:

0.00495

GnomAD4 exome

AF:

0.00528

AC:

7695

AN:

1458562

Hom.:

AF XY:

0.00510

AC XY:

3701

AN XY:

725464

show subpopulations

Gnomad4 AFR exome

AF:

0.000628

Gnomad4 AMR exome

AF:

0.00399

Gnomad4 ASJ exome

AF:

0.00257

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00124

Gnomad4 FIN exome

AF:

0.0166

Gnomad4 NFE exome

AF:

0.00552

Gnomad4 OTH exome

AF:

0.00538

GnomAD4 genome

AF:

0.00483

AC:

736

AN:

152298

Hom.:

Cov.:

AF XY:

0.00508

AC XY:

378

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00582

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0158

Gnomad4 NFE

AF:

0.00609

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00585

Hom.:

Bravo

AF:

0.00381

EpiCase

AF:

0.00567

EpiControl

AF:

0.00605

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RTEL1: PM4:Supporting, BS2; RTEL1-TNFRSF6B: BS2 -

Jul 05, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Aug 28, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely 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 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RTEL1-related disorder

Benign:1

Jun 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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