20-63692975-G-C

Position:

chr20-63692975-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001283009.2(RTEL1):c.2823G>C(p.Glu941Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00617 in 1,612,596 control chromosomes in the GnomAD database, including 515 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 258 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 257 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.291

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:

RTEL1 (HGNC:):

RTEL1 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=0.0016821921).

BP6

Variant 20-63692975-G-C is Benign according to our data. Variant chr20-63692975-G-C is described in ClinVar as [Benign]. Clinvar id is 473916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTEL1	NM_001283009.2 linkuse as main transcript	c.2823G>C	p.Glu941Asp	missense_variant	29/35	ENST00000360203.11	NP_001269938.1	Q9NZ71-6R4IXY3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RTEL1	ENST00000360203.11 linkuse as main transcript	c.2823G>C	p.Glu941Asp	missense_variant	29/35	5	NM_001283009.2	ENSP00000353332.5	Q9NZ71-6
RTEL1	ENST00000508582.7 linkuse as main transcript	c.2895G>C	p.Glu965Asp	missense_variant	29/35	2		ENSP00000424307.2	Q9NZ71-7
RTEL1	ENST00000370018.7 linkuse as main transcript	c.2823G>C	p.Glu941Asp	missense_variant	29/35	1		ENSP00000359035.3	Q9NZ71-1
RTEL1-TNFRSF6B	ENST00000492259.6 linkuse as main transcript	n.*425G>C		non_coding_transcript_exon_variant	26/35	5		ENSP00000457428.1	D6RA96
RTEL1-TNFRSF6B	ENST00000492259 linkuse as main transcript	n.*425G>C		3_prime_UTR_variant	26/35	5		ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes

AF:

0.0312

AC:

4741

AN:

152192

Hom.:

257

Cov.:

show subpopulations

Gnomad AFR

AF:

0.107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.0234

GnomAD3 exomes

AF:

0.00798

AC:

1990

AN:

249522

Hom.:

105

AF XY:

0.00552

AC XY:

748

AN XY:

135468

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.00527

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000339

Gnomad OTH exome

AF:

0.00460

GnomAD4 exome

AF:

0.00356

AC:

5194

AN:

1460286

Hom.:

257

Cov.:

AF XY:

0.00306

AC XY:

2220

AN XY:

726446

show subpopulations

Gnomad4 AFR exome

AF:

0.117

Gnomad4 AMR exome

AF:

0.00655

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000383

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000416

Gnomad4 OTH exome

AF:

0.00774

GnomAD4 genome

AF:

0.0312

AC:

4757

AN:

152310

Hom.:

258

Cov.:

AF XY:

0.0300

AC XY:

2235

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.108

Gnomad4 AMR

AF:

0.0141

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.00356

Hom.:

Bravo

AF:

0.0361

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.102

AC:

448

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00976

AC:

1179

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000534

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

Dyskeratosis congenita

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;.;.;.

Eigen

Benign

-0.032

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.64

T;T;T;T

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;.;M;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.9

N;N;N;.

REVEL

Benign

0.075

Sift

Benign

0.091

T;T;T;.

Sift4G

Benign

0.13

T;T;T;T

Polyphen

0.61

P;D;P;.

Vest4

0.22

MutPred

0.33

Loss of ubiquitination at K944 (P = 0.0656);.;Loss of ubiquitination at K944 (P = 0.0656);.;

MVP

0.35

ClinPred

0.027

GERP RS

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.37

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