rs143461704

Positions:

chr20-63661440-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001283009.2(RTEL1):c.245C>T(p.Pro82Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000942 in 1,613,490 control chromosomes in the GnomAD database, including 2 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 2 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: -0.368

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:):

RTEL1-TNFRSF6B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.043679267).

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTEL1	NM_001283009.2 linkuse as main transcript	c.245C>T	p.Pro82Leu	missense_variant	3/35	ENST00000360203.11	NP_001269938.1
RTEL1-TNFRSF6B	NR_037882.1 linkuse as main transcript	n.1072C>T		non_coding_transcript_exon_variant	3/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11 linkuse as main transcript	c.245C>T	p.Pro82Leu	missense_variant	3/35	5	NM_001283009.2	ENSP00000353332	A2	Q9NZ71-6

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000299

AC:

AN:

250654

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.000600

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000998

AC:

1459

AN:

1461334

Hom.:

Cov.:

AF XY:

0.000970

AC XY:

705

AN XY:

726986

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000567

Gnomad4 NFE exome

AF:

0.00121

Gnomad4 OTH exome

AF:

0.00169

GnomAD4 genome

AF:

0.000401

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000776

Hom.:

Bravo

AF:

0.000434

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 23, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 82 of the RTEL1 protein (p.Pro82Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with aplastic anemia (PMID: 29344583, 30523342). ClinVar contains an entry for this variant (Variation ID: 436585). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RTEL1 function (PMID: 29344583). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 07, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 15, 2016

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2022

The c.245C>T (p.P82L) alteration is located in exon 3 (coding exon 2) of the RTEL1 gene. This alteration results from a C to T substitution at nucleotide position 245, causing the proline (P) at amino acid position 82 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Dyskeratosis congenita, autosomal dominant 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jun 15, 2020

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 13, 2024

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: normal overall telomere length but erosion of the 3' overhang, and normal regulation of TRF2 in patient peripheral blood cells but increased TRF2 expression in a 293T cell line (PMID: 29344583); Observed in an individual with aplastic anemia and in their unaffected brother, as well as in an unrelated individual with acute myelogenous leukemia and in their brother with thrombocytopenia (PMID: 29344583, 30523342); This variant is associated with the following publications: (PMID: 29344583, 30523342, 36496180) -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Jun 02, 2022

This RTEL1 missense variant has been reported in the literature in an individual with aplastic anemia and the individual's sibling with thrombocytopenia. This variant (rs143461704) is rare (<0.1%) in a large population dataset (gnomAD v3.1.2: 61/152156 total alleles; 0.04%; no homozygotes), and has been reported in ClinVar (Variation ID 436585). Of three bioinformatics tools queried, one predicts that the substitution would be damaging, while two predict that it would be tolerated. While the proline residue at this position is evolutionarily conserved across many of the species assessed, leucine is present at this position in multiple species. Functional studies performed were inconclusive. We consider the clinical significance of c.245C>T to be uncertain at this time. -

RTEL1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2024

The RTEL1 c.245C>T variant is predicted to result in the amino acid substitution p.Pro82Leu. This variant has been reported in an individual with moderate aplastic anemia and mitral valve prolapse (Marsh et al. 2018. PubMed ID: 29344583). This variant was also reported in two siblings with aplastic anemia and normal telomere length (Patients NIH078 and NIH079 in Supplemental Table S3, Gutierrez-Rodrigues et al. 2019. PubMed ID: 30523342). This variant is reported in 0.061% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/436585). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.050

DANN

Benign

0.78

DEOGEN2

Uncertain

0.52

D;.;.;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.66

T;T;T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.044

T;T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.1

L;L;L;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-3.1

D;D;D;D;.

REVEL

Benign

0.27

Sift

Benign

0.59

T;T;T;T;.

Sift4G

Benign

0.50

T;T;T;T;.

Polyphen

0.0020

B;B;B;.;.

Vest4

0.12

MVP

0.51

ClinPred

0.027

GERP RS

-9.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.033

gMVP

0.51

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