20-63693266-C-T

Position:

chr20-63693266-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001283009.2(RTEL1):c.2975C>T(p.Pro992Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,611,800 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 6 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.461

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00494954).

BP6

Variant 20-63693266-C-T is Benign according to our data. Variant chr20-63693266-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 436575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63693266-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0011 (1606/1459670) while in subpopulation MID AF= 0.00956 (55/5756). AF 95% confidence interval is 0.00754. There are 6 homozygotes in gnomad4_exome. There are 903 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTEL1	NM_001283009.2 link	c.2975C>T	p.Pro992Leu	missense_variant	30/35	ENST00000360203.11	NP_001269938.1	Q9NZ71-6R4IXY3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RTEL1	ENST00000360203.11 link	c.2975C>T	p.Pro992Leu	missense_variant	30/35	5	NM_001283009.2	ENSP00000353332.5	Q9NZ71-6
RTEL1	ENST00000508582.7 link	c.3047C>T	p.Pro1016Leu	missense_variant	30/35	2		ENSP00000424307.2	Q9NZ71-7
RTEL1	ENST00000370018.7 link	c.2975C>T	p.Pro992Leu	missense_variant	30/35	1		ENSP00000359035.3	Q9NZ71-1
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.*577C>T		non_coding_transcript_exon_variant	27/35	5		ENSP00000457428.1	D6RA96
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.*577C>T		3_prime_UTR_variant	27/35	5		ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes

AF:

0.000928

AC:

141

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000983

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000662

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00145

AC:

360

AN:

247790

Hom.:

AF XY:

0.00170

AC XY:

229

AN XY:

134658

show subpopulations

Gnomad AFR exome

AF:

0.000810

Gnomad AMR exome

AF:

0.000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00631

Gnomad FIN exome

AF:

0.000604

Gnomad NFE exome

AF:

0.000803

Gnomad OTH exome

AF:

0.00330

GnomAD4 exome

AF:

0.00110

AC:

1606

AN:

1459670

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

903

AN XY:

726138

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.00579

Gnomad4 FIN exome

AF:

0.000616

Gnomad4 NFE exome

AF:

0.000755

Gnomad4 OTH exome

AF:

0.00164

GnomAD4 genome

AF:

0.000927

AC:

141

AN:

152130

Hom.:

Cov.:

AF XY:

0.000888

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.000982

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00393

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.000662

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000325

Hom.:

Bravo

AF:

0.000929

ESP6500AA

AF:

0.000684

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.00154

AC:

185

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2020	This variant is associated with the following publications: (PMID: 30842500, 29344583) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	RTEL1: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Dyskeratosis congenita

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 18, 2019	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 18, 2021	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 26, 2017

- -

Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

RTEL1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

4.4

DANN

Benign

0.81

DEOGEN2

Benign

0.11

T;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.69

T;T;T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.0049

T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

-0.20

N;.;N;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.83

N;N;N;.

REVEL

Benign

0.17

Sift

Benign

0.47

T;T;T;.

Sift4G

Benign

0.53

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.12

MVP

0.36

ClinPred

0.0011

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.026

gMVP

0.25

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over