rs201540674

chr20-63695619-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1264C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 1.50

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-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]

ACMG classification

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/exons	MANE	UniProt
RTEL1	NM_001283009.2	c.3791G>A	p.Arg1264His	missense_variant	34/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1	n.4618G>A		non_coding_transcript_exon_variant	34/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.3791G>A	p.Arg1264His	missense_variant	34/35	5	NM_001283009.2	A2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152204 Hom.: 0 Cov.: 33

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: 39 AN: 247320 Hom.: 0 AF XY: 0.000178 AC XY: 24 AN XY: 134780

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.: 0 Cov.: 34 AF XY: 0.0000813 AC XY: 59 AN XY: 726002

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: 11 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74354

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.: 0

Bravo AF: 0.000117

ExAC AF: 0.0000749 AC: 9

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dyskeratosis congenita, autosomal recessive 5 Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 15, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 03, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 23, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

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

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Mar 22, 2023	- -

Dyskeratosis congenita Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 20, 2019	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 03, 2019	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2023	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 23, 2021	- -

Interstitial lung disease 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

University of Washington Center for Mendelian Genomics, University of Washington

May 19, 2015

- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2021

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

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Feb 09, 2022

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

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 15, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.084	T
MetaSVM	Uncertain	-0.19	T
MutationTaster	Benign	1.0	D;D;N;N;N
PROVEAN	Benign	-0.88	N
REVEL	Uncertain	0.64
Sift	Uncertain	0.011	D
Sift4G	Benign	0.12	T
Polyphen		0.99	D
Vest4		0.42
MVP		0.74
ClinPred		0.77	D
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

Other links and lift over

dbSNP: rs201540674; hg19: chr20-62326972;