rs35640778

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001283009.2(RTEL1):c.2051G>A(p.Arg684Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,612,098 control chromosomes in the GnomAD database, including 301 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R684W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 14 hom., cov: 33)

Exomes 𝑓: 0.018 ( 287 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.02

Publications

23 publications found

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0063221157).

BP6

Variant 20-63689775-G-A is Benign according to our data. Variant chr20-63689775-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473912.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 = 0.0117 (1786/152264) while in subpopulation NFE AF = 0.0182 (1236/67998). AF 95% confidence interval is 0.0173. There are 14 homozygotes in GnomAd4. There are 832 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2 link	c.2051G>A	p.Arg684Gln	missense_variant	Exon 24 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.2051G>A	p.Arg684Gln	missense_variant	Exon 24 of 35	5	NM_001283009.2	ENSP00000353332.5	Q9NZ71-6
RTEL1	ENST00000508582.7 link	c.2123G>A	p.Arg708Gln	missense_variant	Exon 24 of 35	2		ENSP00000424307.2	Q9NZ71-7
RTEL1	ENST00000370018.7 link	c.2051G>A	p.Arg684Gln	missense_variant	Exon 24 of 35	1		ENSP00000359035.3	Q9NZ71-1
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.2135G>A		non_coding_transcript_exon_variant	Exon 22 of 35	5		ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes

AF:

0.0117

AC:

1786

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00785

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0126

Gnomad FIN

AF:

0.0178

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0182

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.0123

AC:

3046

AN:

247198

AF XY:

0.0133

show subpopulations

Gnomad AFR exome

AF:

0.00221

Gnomad AMR exome

AF:

0.00455

Gnomad ASJ exome

AF:

0.00404

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.0154

Gnomad NFE exome

AF:

0.0185

Gnomad OTH exome

AF:

0.0142

GnomAD4 exome

AF:

0.0178

AC:

26007

AN:

1459834

Hom.:

287

Cov.:

AF XY:

0.0178

AC XY:

12893

AN XY:

726258

show subpopulations

African (AFR)

AF:

0.00215

AC:

AN:

33476

American (AMR)

AF:

0.00523

AC:

234

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00406

AC:

106

AN:

26114

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39694

South Asian (SAS)

AF:

0.0127

AC:

1097

AN:

86252

European-Finnish (FIN)

AF:

0.0139

AC:

720

AN:

51792

Middle Eastern (MID)

AF:

0.0189

AC:

109

AN:

5764

European-Non Finnish (NFE)

AF:

0.0204

AC:

22724

AN:

1111698

Other (OTH)

AF:

0.0156

AC:

942

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

1342

2684

4025

5367

6709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

874

1748

2622

3496

4370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0117

AC:

1786

AN:

152264

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

832

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00325

AC:

135

AN:

41562

American (AMR)

AF:

0.00784

AC:

120

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5160

South Asian (SAS)

AF:

0.0129

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0178

AC:

189

AN:

10626

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0182

AC:

1236

AN:

67998

Other (OTH)

AF:

0.0118

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

191

286

382

477

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0141

Hom.:

Bravo

AF:

0.0107

TwinsUK

AF:

0.0213

AC:

ALSPAC

AF:

0.0192

AC:

ESP6500AA

AF:

0.00319

AC:

ESP6500EA

AF:

0.0177

AC:

152

ExAC

AF:

0.0129

AC:

1552

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0191

EpiControl

AF:

0.0192

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 30, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RTEL1: BP4, BS1, BS2 -

not specified

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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

- -

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

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 18, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

0.095

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

T;.;.;.;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.91

D;D;D;D;D

MetaRNN

Benign

0.0063

T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.77

N;.;N;.;.

PhyloP100

2.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.1

N;N;N;.;N

REVEL

Benign

0.19

Sift

Benign

0.77

T;T;T;.;T

Sift4G

Benign

0.46

T;T;T;T;T

Polyphen

0.18

B;B;B;.;.

Vest4

0.12

ClinPred

0.0070

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.044

gMVP

0.39

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over