rs76364377

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_StrongBA1

The NM_001283009.2(RTEL1):c.1482-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0624 in 1,612,066 control chromosomes in the GnomAD database, including 3,568 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.046 ( 244 hom., cov: 33)

Exomes 𝑓: 0.064 ( 3324 hom. )

Consequence

RTEL1
NM_001283009.2 splice_region, intron

Scores

Splicing: ADA: 0.0001018

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.05

Publications

5 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 (BayesDel_noAF=-0.8).

BP6

Variant 20-63687931-G-A is Benign according to our data. Variant chr20-63687931-G-A is described in ClinVar as Benign. ClinVar VariationId is 473905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2 link	c.1482-6G>A		splice_region_variant, intron_variant	Intron 17 of 34	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
RTEL1	ENST00000360203.11 link	c.1482-6G>A	splice_region_variant, intron_variant	Intron 17 of 34	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7 link	c.1554-6G>A	splice_region_variant, intron_variant	Intron 17 of 34	2		ENSP00000424307.2
RTEL1	ENST00000370018.7 link	c.1482-6G>A	splice_region_variant, intron_variant	Intron 17 of 34	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.1566-6G>A	splice_region_variant, intron_variant	Intron 15 of 34	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes

AF:

0.0464

AC:

7057

AN:

152148

Hom.:

244

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0128

Gnomad AMI

AF:

0.0866

Gnomad AMR

AF:

0.0407

Gnomad ASJ

AF:

0.0207

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0445

Gnomad FIN

AF:

0.0440

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0732

Gnomad OTH

AF:

0.0430

GnomAD2 exomes

AF:

0.0474

AC:

11804

AN:

248810

AF XY:

0.0486

show subpopulations

Gnomad AFR exome

AF:

0.0111

Gnomad AMR exome

AF:

0.0283

Gnomad ASJ exome

AF:

0.0206

Gnomad EAS exome

AF:

0.000708

Gnomad FIN exome

AF:

0.0472

Gnomad NFE exome

AF:

0.0676

Gnomad OTH exome

AF:

0.0539

GnomAD4 exome

AF:

0.0641

AC:

93508

AN:

1459800

Hom.:

3324

Cov.:

AF XY:

0.0637

AC XY:

46281

AN XY:

726186

show subpopulations

African (AFR)

AF:

0.0105

AC:

352

AN:

33464

American (AMR)

AF:

0.0287

AC:

1285

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0209

AC:

547

AN:

26132

East Asian (EAS)

AF:

0.000504

AC:

AN:

39688

South Asian (SAS)

AF:

0.0494

AC:

4258

AN:

86238

European-Finnish (FIN)

AF:

0.0514

AC:

2675

AN:

52058

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0729

AC:

81064

AN:

1111406

Other (OTH)

AF:

0.0538

AC:

3248

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

5003

10006

15010

20013

25016

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2970

5940

8910

11880

14850

<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:

0.0463

AC:

7050

AN:

152266

Hom.:

244

Cov.:

AF XY:

0.0454

AC XY:

3384

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0127

AC:

529

AN:

41544

American (AMR)

AF:

0.0406

AC:

621

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0207

AC:

AN:

3470

East Asian (EAS)

AF:

0.000966

AC:

AN:

5178

South Asian (SAS)

AF:

0.0439

AC:

212

AN:

4824

European-Finnish (FIN)

AF:

0.0440

AC:

467

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0732

AC:

4976

AN:

68000

Other (OTH)

AF:

0.0421

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

335

670

1006

1341

1676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0574

Hom.:

208

Bravo

AF:

0.0421

Asia WGS

AF:

0.0290

AC:

AN:

3478

EpiCase

AF:

0.0682

EpiControl

AF:

0.0629

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

- -

Mar 01, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.1554-6G>A in intron 17 of RTEL1: This variant is not expected to have clinical significance because it has been identified in 7% (8722/125530) of European chr omosomes by the Genome Aggregation Databse (gnomAD, http://exac.broadinstitute.o rg; dbSNP rs76364377). ACMG/AMP Criteria applied: BA1; BP4. -

not provided

Benign:3

Feb 02, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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 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

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.1

(source)

DANN

Benign

0.50

PhyloP100

-1.0

PromoterAI

0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00010

dbscSNV1_RF

Benign

0.048

SpliceAI score (max)

0.080

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