rs150461578

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001283009.2(RTEL1):c.2444G>T(p.Ser815Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,605,996 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S815G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 7 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.958

Publications

8 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042290688).

BP6

Variant 20-63690835-G-T is Benign according to our data. Variant chr20-63690835-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540960.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2 link	c.2444G>T	p.Ser815Ile	missense_variant	Exon 27 of 35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RTEL1	ENST00000360203.11 link	c.2444G>T	p.Ser815Ile	missense_variant	Exon 27 of 35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7 link	c.2516G>T	p.Ser839Ile	missense_variant	Exon 27 of 35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7 link	c.2444G>T	p.Ser815Ile	missense_variant	Exon 27 of 35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.*46G>T		non_coding_transcript_exon_variant	Exon 24 of 35	5		ENSP00000457428.1
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.*46G>T		3_prime_UTR_variant	Exon 24 of 35	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes

AF:

0.00175

AC:

266

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00584

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00229

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00165

AC:

393

AN:

237664

AF XY:

0.00166

show subpopulations

Gnomad AFR exome

AF:

0.000275

Gnomad AMR exome

AF:

0.00128

Gnomad ASJ exome

AF:

0.000416

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00652

Gnomad NFE exome

AF:

0.00186

Gnomad OTH exome

AF:

0.00242

GnomAD4 exome

AF:

0.00171

AC:

2482

AN:

1453780

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

1220

AN XY:

722742

show subpopulations

African (AFR)

AF:

0.000390

AC:

AN:

33342

American (AMR)

AF:

0.00159

AC:

AN:

44122

Ashkenazi Jewish (ASJ)

AF:

0.000541

AC:

AN:

25894

East Asian (EAS)

AF:

0.00

AC:

AN:

39598

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85234

European-Finnish (FIN)

AF:

0.00689

AC:

354

AN:

51416

Middle Eastern (MID)

AF:

0.00165

AC:

AN:

4230

European-Non Finnish (NFE)

AF:

0.00175

AC:

1939

AN:

1109998

Other (OTH)

AF:

0.00140

AC:

AN:

59946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

132

265

397

530

662

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.00175

AC:

266

AN:

152216

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

154

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41538

American (AMR)

AF:

0.00144

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00584

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00230

AC:

156

AN:

67972

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00177

Hom.:

Bravo

AF:

0.00152

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00115

AC:

ESP6500EA

AF:

0.000700

AC:

ExAC

AF:

0.00119

AC:

143

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RTEL1: BP4, BS1, BS2 -

Dec 13, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Likely 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

Uncertain:1Benign:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RTEL1 NM_032957.4 exon 27 p.Ser839Ile (c.2516G>T): This variant has not been reported in the literature but is present in 0.6% (150/23244) of Finnish alleles, including 2 homozygotes, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/20-62322188-G-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:540960). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RTEL1-related disorder

Benign:1

May 15, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Dyskeratosis congenita

Benign:1

Mar 02, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

D;.;.;.;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.83

T;T;T;T;T

MetaRNN

Benign

0.0042

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;.;M;.;.

PhyloP100

0.96

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.4

D;D;D;.;D

REVEL

Benign

0.047

Sift

Benign

0.037

D;D;D;.;D

Sift4G

Benign

0.072

T;T;T;T;D

Polyphen

0.075

B;P;B;.;.

Vest4

0.46

MVP

0.36

ClinPred

0.034

GERP RS

1.7

Varity_R

0.13

gMVP

0.41

Mutation Taster

=95/5

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

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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