chr20-63694757-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001283009.2(RTEL1):c.3126A>C(p.Gln1042His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.757 in 1,603,768 control chromosomes in the GnomAD database, including 465,486 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1042Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.81 ( 50454 hom., cov: 34)

Exomes 𝑓: 0.75 ( 415032 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: -0.643

Publications

54 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=9.625584E-7).

BP6

Variant 20-63694757-A-C is Benign according to our data. Variant chr20-63694757-A-C is described in ClinVar as Benign. ClinVar VariationId is 403402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 link	c.3126A>C	p.Gln1042His	missense_variant	Exon 32 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.3126A>C	p.Gln1042His	missense_variant	Exon 32 of 35	5	NM_001283009.2	ENSP00000353332.5	Q9NZ71-6
RTEL1	ENST00000508582.7 link	c.3198A>C	p.Gln1066His	missense_variant	Exon 32 of 35	2		ENSP00000424307.2	Q9NZ71-7
RTEL1	ENST00000370018.7 link	c.3126A>C	p.Gln1042His	missense_variant	Exon 32 of 35	1		ENSP00000359035.3	Q9NZ71-1
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.*728A>C		non_coding_transcript_exon_variant	Exon 29 of 35	5		ENSP00000457428.1	D6RA96
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.*728A>C		3_prime_UTR_variant	Exon 29 of 35	5		ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes

AF:

0.806

AC:

122554

AN:

152106

Hom.:

50397

Cov.:

show subpopulations

Gnomad AFR

AF:

0.937

Gnomad AMI

AF:

0.768

Gnomad AMR

AF:

0.788

Gnomad ASJ

AF:

0.769

Gnomad EAS

AF:

0.370

Gnomad SAS

AF:

0.737

Gnomad FIN

AF:

0.799

Gnomad MID

AF:

0.797

Gnomad NFE

AF:

0.771

Gnomad OTH

AF:

0.802

GnomAD2 exomes

AF:

0.748

AC:

181757

AN:

242878

AF XY:

0.749

show subpopulations

Gnomad AFR exome

AF:

0.943

Gnomad AMR exome

AF:

0.751

Gnomad ASJ exome

AF:

0.771

Gnomad EAS exome

AF:

0.357

Gnomad FIN exome

AF:

0.801

Gnomad NFE exome

AF:

0.774

Gnomad OTH exome

AF:

0.761

GnomAD4 exome

AF:

0.752

AC:

1091745

AN:

1451544

Hom.:

415032

Cov.:

AF XY:

0.752

AC XY:

542105

AN XY:

720928

show subpopulations

African (AFR)

AF:

0.949

AC:

31547

AN:

33234

American (AMR)

AF:

0.752

AC:

33151

AN:

44104

Ashkenazi Jewish (ASJ)

AF:

0.772

AC:

20039

AN:

25958

East Asian (EAS)

AF:

0.378

AC:

14905

AN:

39440

South Asian (SAS)

AF:

0.745

AC:

64083

AN:

86024

European-Finnish (FIN)

AF:

0.800

AC:

40325

AN:

50410

Middle Eastern (MID)

AF:

0.799

AC:

4580

AN:

5730

European-Non Finnish (NFE)

AF:

0.757

AC:

838223

AN:

1106718

Other (OTH)

AF:

0.749

AC:

44892

AN:

59926

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

13908

27816

41725

55633

69541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20212

40424

60636

80848

101060

<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:

0.806

AC:

122673

AN:

152224

Hom.:

50454

Cov.:

AF XY:

0.804

AC XY:

59794

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.938

AC:

38986

AN:

41580

American (AMR)

AF:

0.788

AC:

12058

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.769

AC:

2668

AN:

3468

East Asian (EAS)

AF:

0.371

AC:

1909

AN:

5148

South Asian (SAS)

AF:

0.737

AC:

3553

AN:

4824

European-Finnish (FIN)

AF:

0.799

AC:

8470

AN:

10604

Middle Eastern (MID)

AF:

0.810

AC:

238

AN:

294

European-Non Finnish (NFE)

AF:

0.771

AC:

52403

AN:

67982

Other (OTH)

AF:

0.798

AC:

1689

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1183

2365

3548

4730

5913

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

858

1716

2574

3432

4290

<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:

0.768

Hom.:

60863

Bravo

AF:

0.807

TwinsUK

AF:

0.755

AC:

2801

ALSPAC

AF:

0.758

AC:

2923

ESP6500AA

AF:

0.930

AC:

4026

ESP6500EA

AF:

0.769

AC:

6574

ExAC

AF:

0.751

AC:

89921

ClinVar

Significance: Benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

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. -

not provided

Benign:4Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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.3198A>C (p.Gln1066His) variant involves the alteration of a non-conserved nucleotide that 4/4 in silico tools predict a benign outcome. This variant was found in 87362/115752 control chromosomes (33743 homozygotes) at a frequency of 0.7547343, which indicates that the C allele is the major allele found in the general population. In addition, a clinical diagnostic laboratory classified this variant as benign. Therefore, due to the allele frequency observed in the general control population, the variant of interest has been 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

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27128385, 23329068) -

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

0.066

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.50

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.064

T;.;.;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.024

T;T;T;T

MetaRNN

Benign

9.6e-7

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.1

N;.;N;.

PhyloP100

-0.64

PrimateAI

Benign

0.36

PROVEAN

Benign

0.19

N;N;N;.

REVEL

Benign

0.17

Sift

Benign

0.25

T;T;T;.

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.036

MutPred

0.029

Gain of glycosylation at S1041 (P = 0.1177);.;Gain of glycosylation at S1041 (P = 0.1177);.;

ClinPred

0.0077

GERP RS

-8.4

Varity_R

0.067

gMVP

0.23

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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