20-63694757-A-C

Position:

chr20-63694757-A-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.3126A>C(p.Gln1042His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.757 in 1,603,768 control chromosomes in the GnomAD database, including 465,486 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.81 ( 50454 hom., cov: 34)

Exomes 𝑓: 0.75 ( 415032 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: -0.643

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=9.625584E-7).

BP6

Variant 20-63694757-A-C is Benign according to our data. Variant chr20-63694757-A-C is described in ClinVar as [Benign]. Clinvar id is 403402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63694757-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.93 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.3126A>C	p.Gln1042His	missense_variant	32/35	ENST00000360203.11	NP_001269938.1
RTEL1-TNFRSF6B	NR_037882.1 linkuse as main transcript	n.3953A>C		non_coding_transcript_exon_variant	32/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11 linkuse as main transcript	c.3126A>C	p.Gln1042His	missense_variant	32/35	5	NM_001283009.2	ENSP00000353332	A2	Q9NZ71-6

Frequencies

GnomAD3 genomes

AF:

0.806

AC:

122554

AN:

152106

Hom.:

50397

Cov.:

show subpopulations

Gnomad AFR

AF:

0.937

Gnomad AMI

AF:

0.768

Gnomad AMR

AF:

0.788

Gnomad ASJ

AF:

0.769

Gnomad EAS

AF:

0.370

Gnomad SAS

AF:

0.737

Gnomad FIN

AF:

0.799

Gnomad MID

AF:

0.797

Gnomad NFE

AF:

0.771

Gnomad OTH

AF:

0.802

GnomAD3 exomes

AF:

0.748

AC:

181757

AN:

242878

Hom.:

69854

AF XY:

0.749

AC XY:

99279

AN XY:

132592

show subpopulations

Gnomad AFR exome

AF:

0.943

Gnomad AMR exome

AF:

0.751

Gnomad ASJ exome

AF:

0.771

Gnomad EAS exome

AF:

0.357

Gnomad SAS exome

AF:

0.742

Gnomad FIN exome

AF:

0.801

Gnomad NFE exome

AF:

0.774

Gnomad OTH exome

AF:

0.761

GnomAD4 exome

AF:

0.752

AC:

1091745

AN:

1451544

Hom.:

415032

Cov.:

AF XY:

0.752

AC XY:

542105

AN XY:

720928

show subpopulations

Gnomad4 AFR exome

AF:

0.949

Gnomad4 AMR exome

AF:

0.752

Gnomad4 ASJ exome

AF:

0.772

Gnomad4 EAS exome

AF:

0.378

Gnomad4 SAS exome

AF:

0.745

Gnomad4 FIN exome

AF:

0.800

Gnomad4 NFE exome

AF:

0.757

Gnomad4 OTH exome

AF:

0.749

GnomAD4 genome

AF:

0.806

AC:

122673

AN:

152224

Hom.:

50454

Cov.:

AF XY:

0.804

AC XY:

59794

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.938

Gnomad4 AMR

AF:

0.788

Gnomad4 ASJ

AF:

0.769

Gnomad4 EAS

AF:

0.371

Gnomad4 SAS

AF:

0.737

Gnomad4 FIN

AF:

0.799

Gnomad4 NFE

AF:

0.771

Gnomad4 OTH

AF:

0.798

Alfa

AF:

0.764

Hom.:

42630

Bravo

AF:

0.807

TwinsUK

AF:

0.755

AC:

2801

ALSPAC

AF:

0.758

AC:

2923

ESP6500AA

AF:

0.930

AC:

4026

ESP6500EA

AF:

0.769

AC:

6574

ExAC

AF:

0.751

AC:

89921

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 89% of patients studied by a panel of primary immunodeficiencies. Number of patients: 85. Only high quality variants are reported. -

not provided

Benign:3Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27128385, 23329068) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 10, 2017	Variant summary: The RTEL1 c.3198A>C (p.Gln1066His) variant involves the alteration of a non-conserved nucleotide that 4/4 in silico tools predict a benign outcome. This variant was found in 87362/115752 control chromosomes (33743 homozygotes) at a frequency of 0.7547343, which indicates that the C allele is the major allele found in the general population. In addition, a clinical diagnostic laboratory classified this variant as benign. Therefore, due to the allele frequency observed in the general control population, the variant of interest has been classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Dyskeratosis congenita, autosomal recessive 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

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

Feb 01, 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

0.066

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.50

DANN

Benign

0.57

DEOGEN2

Benign

0.064

T;.;.;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.024

T;T;T;T

MetaRNN

Benign

9.6e-7

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.1

N;.;N;.

MutationTaster

Benign

1.0

P;P;P;P;P

PrimateAI

Benign

0.36

PROVEAN

Benign

0.19

N;N;N;.

REVEL

Benign

0.17

Sift

Benign

0.25

T;T;T;.

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.036

MutPred

0.029

Gain of glycosylation at S1041 (P = 0.1177);.;Gain of glycosylation at S1041 (P = 0.1177);.;

ClinPred

0.0077

GERP RS

-8.4

Varity_R

0.067

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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