rs115610405

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.3101C>A(p.Pro1034His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,597,222 control chromosomes in the GnomAD database, including 342 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. P1034S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.016 ( 43 hom., cov: 31)

Exomes 𝑓: 0.018 ( 299 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.196

Publications

11 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=0.0027760863).

BP6

Variant 20-63694480-C-A is Benign according to our data. Variant chr20-63694480-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473917.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 = 0.0158 (2402/152326) while in subpopulation NFE AF = 0.0201 (1367/68028). AF 95% confidence interval is 0.0192. There are 43 homozygotes in GnomAd4. There are 1222 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 43 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2 link	c.3101C>A	p.Pro1034His	missense_variant	Exon 31 of 35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RTEL1	ENST00000360203.11 link	c.3101C>A	p.Pro1034His	missense_variant	Exon 31 of 35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7 link	c.3173C>A	p.Pro1058His	missense_variant	Exon 31 of 35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7 link	c.3101C>A	p.Pro1034His	missense_variant	Exon 31 of 35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.*703C>A		non_coding_transcript_exon_variant	Exon 28 of 35	5		ENSP00000457428.1
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.*703C>A		3_prime_UTR_variant	Exon 28 of 35	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes

AF:

0.0158

AC:

2401

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00415

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.0143

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.0517

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0201

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0161

AC:

3944

AN:

244392

AF XY:

0.0163

show subpopulations

Gnomad AFR exome

AF:

0.00338

Gnomad AMR exome

AF:

0.00830

Gnomad ASJ exome

AF:

0.00688

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0474

Gnomad NFE exome

AF:

0.0219

Gnomad OTH exome

AF:

0.0208

GnomAD4 exome

AF:

0.0182

AC:

26335

AN:

1444896

Hom.:

299

Cov.:

AF XY:

0.0178

AC XY:

12761

AN XY:

715800

show subpopulations

African (AFR)

AF:

0.00280

AC:

AN:

33166

American (AMR)

AF:

0.00908

AC:

401

AN:

44152

Ashkenazi Jewish (ASJ)

AF:

0.00711

AC:

184

AN:

25888

East Asian (EAS)

AF:

0.00

AC:

AN:

39222

South Asian (SAS)

AF:

0.000793

AC:

AN:

85774

European-Finnish (FIN)

AF:

0.0461

AC:

2395

AN:

51916

Middle Eastern (MID)

AF:

0.00350

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.0202

AC:

22177

AN:

1099448

Other (OTH)

AF:

0.0167

AC:

997

AN:

59620

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1249

2499

3748

4998

6247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

810

1620

2430

3240

4050

<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:

0.0158

AC:

2402

AN:

152326

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1222

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00414

AC:

172

AN:

41580

American (AMR)

AF:

0.0144

AC:

220

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00518

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000623

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0517

AC:

549

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0201

AC:

1367

AN:

68028

Other (OTH)

AF:

0.0114

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

120

240

361

481

601

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0185

Hom.:

Bravo

AF:

0.0131

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0197

AC:

ESP6500AA

AF:

0.00574

AC:

ESP6500EA

AF:

0.0191

AC:

163

ExAC

AF:

0.0159

AC:

1911

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0192

EpiControl

AF:

0.0202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 29, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

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:1

Feb 03, 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

0.077

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

8.0

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

T;.;.;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.58

T;T;T;T

MetaRNN

Benign

0.0028

T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.6

L;.;L;.

PhyloP100

-0.20

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.2

N;N;N;.

REVEL

Benign

0.26

Sift

Benign

0.40

T;T;T;.

Sift4G

Benign

0.35

T;T;T;T

Polyphen

0.94

P;D;D;.

Vest4

0.26

ClinPred

0.0065

GERP RS

-0.64

Varity_R

0.080

gMVP

0.23

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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