chr20-63695619-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

The NM_001283009.2(RTEL1):c.3791G>A(p.Arg1264His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000782 in 1,611,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16O:1

Conservation

PhyloP100: 1.50

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 Likely_pathogenic. Variant got 7 ACMG points.

PP5

Variant 20-63695619-G-A is Pathogenic according to our data. Variant chr20-63695619-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63695619-G-A is described in Lovd as [Pathogenic]. Variant chr20-63695619-G-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.08357221). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2 link	c.3791G>A	p.Arg1264His	missense_variant	Exon 34 of 35	ENST00000360203.11	NP_001269938.1	Q9NZ71-6R4IXY3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RTEL1	ENST00000360203.11 link	c.3791G>A	p.Arg1264His	missense_variant	Exon 34 of 35	5	NM_001283009.2	ENSP00000353332.5	Q9NZ71-6
RTEL1	ENST00000508582.7 link	c.3724+139G>A		intron_variant	Intron 34 of 34	2		ENSP00000424307.2	Q9NZ71-7
RTEL1	ENST00000370018.7 link	c.3652+139G>A		intron_variant	Intron 34 of 34	1		ENSP00000359035.3	Q9NZ71-1
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.*1254+139G>A		intron_variant	Intron 31 of 34	5		ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000158

AC:

AN:

247320

Hom.:

AF XY:

0.000178

AC XY:

AN XY:

134780

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00342

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000449

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000788

AC:

115

AN:

1459298

Hom.:

Cov.:

AF XY:

0.0000813

AC XY:

AN XY:

726002

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00325

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000263

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.0000749

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dyskeratosis congenita, autosomal recessive 5

Pathogenic:3Other:1

Oct 23, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 03, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided

Pathogenic:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 23, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 24, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a significant increase in telomere loss and increase in cells with telomere dysfunction-induced foci (Sarek et al., 2015); Observed in the heterozygous state in individuals reported to be clinically unaffected, as well as individuals with a history of pulmonary fibrosis or myelodysplastic syndrome in individuals referred for genetic testing at GeneDx and in published literature (Ballew et al., 2013; Walne et al., 2013; Cogan et al., 2015; Hanna et al., 2015); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 30088779, 23453664, 25047097, 24009516, 25607374, 26025130, 28507545, 27415407, 32135276, 32710398, 34021146, 32561545, 28104920, 25099625, 34308104, 25620558) -

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

Pathogenic:3

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1264 of the RTEL1 protein (p.Arg1264His). This variant is present in population databases (rs201540674, gnomAD 0.3%). This missense change has been observed in individuals with RTEL1-related conditions (PMID: 23453664, 24009516, 25047097, 25099625, 26025130). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 23453664, 24009516, 25047097, 25099625, 26025130). This variant is also known as c.3724+139G>A on transcript NM_032957.4. ClinVar contains an entry for this variant (Variation ID: 42018). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RTEL1 function (PMID: 24009516, 25620558). For these reasons, this variant has been classified as Pathogenic. -

Mar 22, 2023

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dyskeratosis congenita

Pathogenic:3

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 03, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg1264His variant in RTEL1 has been reported in the homozygous state in 4 individuals with Dyskeratosis Congenita (DC) or Hoyeraal Hreidarsson (HH), a severe form of DC (Ballwe 2013, Gueye 2014, Hanna 2015). It has also been identified in the compound heterozygous state with another missense variant in an individual with HH (Walne 2013). In addition, this variant was identified in the heterozygous state in 2 siblings with pulmonary fibrosis (Cogan 2015). Although some variants in RTEL1 have been reported to be associated with increased risk for developing pulmonary fibrosis or other isolated features of DC, additional evidence would be needed to determine if this variant confers a risk for disease in the heterozgous state. This variant has also been identified in 0.35% (36/10234) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org), and a carrier screening study identified the variant in 1% of the orthodox Ashkenazi Jewish population and 0.45% of the general Ashkenazi Jewish population (Fedick 2015). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein; however, in vitro functional studies suggest that this variant impacts protein function (Sarek 2015). In summary, although the allele frequency of this variant in the Ashkenazi Jewish population of gnomAD is higher than the expected maximum allele frequency for a pathogenic variant in RTEL1, this variant meets criteria to be classified as likely pathogenic for autosomal recessive dyskeratosis congenita. ACMG/AMP Criteria applied: PM3_Strong, PS3_Moderate, PP4, BS1. -

Sep 20, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary:RTEL1 NM_032957.4:c.3724+139G>A, also known as c.3791G>A (p.Arg1264His) in NM_001283009.1 (rs201540674), is located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. Arg1264 is highly conserved and is centrally located within the putative C4C4 Zn2+ coordination domain of the encoded protein. In silico prediction algorithms (SIFT, PolyPhen-2, and Condel) indicate that this amino acid substitution is likely to be damaging to the protein (Ballew_2013). The variant allele was found at a frequency of 0.00016 in 247320 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RTEL1 causing Dyskeratosis Congenita (Hoyeraal Hreidarsson Syndrome) (0.00016 vs 0.0011), allowing no conclusion about variant significance. c.3724+139G>A has been reported in the literature in multiple individuals affected with Dyskeratosis Congenita (Hoyeraal Hreidarsson Syndrome)(Walne_2013, Ballew_2013) including at-least one ascertained report of its homozygous presence in an individual with isolated natural killer cell deficiency (Hanna_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C (Ballew_2013). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All clinical diagnostic laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Interstitial lung disease 2

Pathogenic:1

May 19, 2015

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Inborn genetic diseases

Pathogenic:1

Jun 14, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3724+139G>A alteration consists of a G to A substitution 139 nucleotides after exon 34 (coding exon 33) in the NM_032957 isoform of the RTEL1 gene. This alteration is also referred to as c.3791G>A (p.R1264H), which is located in exon 34 (coding exon 33) in the NM_001283009 isoform of the RTEL1 gene, and results from a G to A substitution at nucleotide position 3791, causing the arginine (A) at amino acid position 1264 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD) database, the RTEL1 c.3724+139G>A alteration was observed in 0.01% (41/278700) of total alleles studied, with a frequency of 0.35% (36/10234) in the Ashkenazi Jewish subpopulation. This alteration has been reported in the homozygous and compound heterozygous states in patients with Hoyeraal-Hreidarsson syndrome and/or immunodeficiency. Heterozygous carriers in these families were reportedly unaffected (Ballew, 2013; Walne, 2013; Hanna, 2015). This alteration has an estimated carrier frequency of 1% in the Ashkenazi Orthodox and 0.45% in the general Ashkenazi Jewish population (Fedick, 2015). This alteration has also been identified in the heterozygous state in two siblings with adult-onset pulmonary fibrosis (Cogan, 2015). Patient-derived cell lines demonstrated deficient function as indicated by telomere length heterogeneity, the presence of extra-chromosomal circular telomeric DNA, hypersensitivity to DNA damage and increased sister chromatid exchange (Ballew, 2013). In addition, both patient-derived cells and mutant mouse embryonic fibroblasts demonstrated compromised RTEL1-TRF2 interaction leading to accumulation of telomere circles and telomere loss (Sarek, 2015). Based on the available evidence, this alteration is classified as likely pathogenic. -

See cases

Pathogenic:1

Feb 09, 2022

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS3,PM3,PP3,PP5,BP1 -

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

Pathogenic:1

Mar 15, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.88

MetaRNN

Benign

0.084

MetaSVM

Uncertain

-0.19

PROVEAN

Benign

-0.88

REVEL

Uncertain

0.64

Sift

Uncertain

0.011

Sift4G

Benign

0.12

Polyphen

0.99

Vest4

0.42

MVP

0.74

ClinPred

0.77

GERP RS

3.7

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

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