20-63659344-A-C

Variant names:

Variant summary

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

The ENST00000492259.6(RTEL1-TNFRSF6B):n.-59A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0537 in 1,320,270 control chromosomes in the GnomAD database, including 2,369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 172 hom., cov: 33)

Exomes 𝑓: 0.056 ( 2197 hom. )

Consequence

RTEL1-TNFRSF6B
ENST00000492259.6 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.119

Publications

12 publications found

Variant links:

Genes affected

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:

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 Gene-Disease associations (from GenCC):

dyskeratosis congenita, autosomal recessive 5
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)
pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
acute myeloid leukemia
Inheritance: AD, AR Classification: MODERATE Submitted by: Genomics England PanelApp
dyskeratosis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hoyeraal-Hreidarsson syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RTEL1 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=-0.82).

BP6

Variant 20-63659344-A-C is Benign according to our data. Variant chr20-63659344-A-C is described in ClinVar as [Benign]. Clinvar id is 1279544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2 link	c.-59A>C		5_prime_UTR_variant	Exon 2 of 35	ENST00000360203.11	NP_001269938.1	Q9NZ71-6R4IXY3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.-59A>C	non_coding_transcript_exon_variant	Exon 1 of 35	5		ENSP00000457428.1	D6RA96
RTEL1	ENST00000360203.11 link	c.-59A>C	5_prime_UTR_variant	Exon 2 of 35	5	NM_001283009.2	ENSP00000353332.5	Q9NZ71-6
RTEL1	ENST00000508582.7 link	c.-59A>C	5_prime_UTR_variant	Exon 2 of 35	2		ENSP00000424307.2	Q9NZ71-7
RTEL1	ENST00000370018.7 link	c.-59A>C	5_prime_UTR_variant	Exon 2 of 35	1		ENSP00000359035.3	Q9NZ71-1
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.-59A>C	5_prime_UTR_variant	Exon 1 of 35	5		ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes

AF:

0.0386

AC:

5873

AN:

152122

Hom.:

172

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0111

Gnomad AMI

AF:

0.101

Gnomad AMR

AF:

0.0174

Gnomad ASJ

AF:

0.0242

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00850

Gnomad FIN

AF:

0.0596

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0622

Gnomad OTH

AF:

0.0298

GnomAD4 exome

AF:

0.0557

AC:

65023

AN:

1168030

Hom.:

2197

Cov.:

AF XY:

0.0537

AC XY:

31875

AN XY:

593646

show subpopulations

African (AFR)

AF:

0.00875

AC:

242

AN:

27664

American (AMR)

AF:

0.0143

AC:

619

AN:

43360

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

516

AN:

24218

East Asian (EAS)

AF:

0.000261

AC:

AN:

38268

South Asian (SAS)

AF:

0.00952

AC:

757

AN:

79490

European-Finnish (FIN)

AF:

0.0579

AC:

3070

AN:

53016

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

4806

European-Non Finnish (NFE)

AF:

0.0679

AC:

57434

AN:

846480

Other (OTH)

AF:

0.0465

AC:

2360

AN:

50728

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

3068

6135

9203

12270

15338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0386

AC:

5870

AN:

152240

Hom.:

172

Cov.:

AF XY:

0.0369

AC XY:

2748

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0110

AC:

458

AN:

41548

American (AMR)

AF:

0.0173

AC:

265

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0242

AC:

AN:

3468

East Asian (EAS)

AF:

0.000578

AC:

AN:

5190

South Asian (SAS)

AF:

0.00830

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0596

AC:

632

AN:

10596

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0622

AC:

4230

AN:

68006

Other (OTH)

AF:

0.0295

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

284

568

853

1137

1421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0530

Hom.:

194

Bravo

AF:

0.0346

Asia WGS

AF:

0.00953

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 07, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.0

(source)

DANN

Benign

0.58

PhyloP100

0.12

Mutation Taster

=300/0

polymorphism

(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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20-63659344-A-C

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