rs587777037

Positions:

• chr20-63695558-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001283009.2(RTEL1):​c.3730T>C​(p.Cys1244Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,460,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:4
• Conservation: PhyloP100: 1.26

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 Uncertain_significance. Variant got 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2	c.3730T>C	p.Cys1244Arg	missense_variant	34/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1	n.4557T>C		non_coding_transcript_exon_variant	34/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.3730T>C	p.Cys1244Arg	missense_variant	34/35	5	NM_001283009.2	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000202 AC: 5 AN: 247318 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135024

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000360

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1460072 Hom.: 0 Cov.: 34 AF XY: 0.0000179 AC XY: 13 AN XY: 726358

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000356 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dyskeratosis congenita, autosomal recessive 5 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 15, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 28, 2017	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2023

The c.3724+78T>C intronic alteration results from a T to C substitution 78 nucleotides after coding exon 33 of the RTEL1 gene._x000D_ _x000D_ _x000D_ _x000D_ The c.3730T>C (p.C1244R) alteration is located in exon 34 (coding exon 33) of the RTEL1 gene. This alteration results from a T to C substitution at nucleotide position 3730, causing the cysteine (C) at amino acid position 1244 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of 0.002% (5/247318) total alleles studied. The highest observed frequency was 0.005% (1/18282) of East Asian alleles. This variant was detected in two affected siblings with shortened telomere length and abnormal telomere function. Both of these siblings were compound heterozygous carriers of this variant as well as RTEL1 c.2097C>G (p.I699M) (Le Guen, 2013). This variant has also been detected in heterozygous form in a 61 year old female with idiopathic pulmonary fibrosis post lung transplant who also had severely shortened telomeres (Popescu, 2019). This nucleotide position is highly conserved in available vertebrate species._x000D_ _x000D_ Leave out nucleotide conservation sentence and table? The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 01, 2017

DNA sequence analysis of the RTEL1 gene demonstrated a sequence change, c.3730T>C, in exon 34 that results in an amino acid change, p.Cys1244Arg. The p.Cys1244Arg change affects a moderately conserved amino acid residue located in a domain of the RTEL1 protein that is known to be functional. The p.Cys1244Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). This variant is present in 5 individuals in gnomAD (0.002% frequency in the global population). This sequence change has been described in the compound heterozygous state with another variant in two siblings with Hoyeraal-Hreidarsson syndrome and not present in their unaffected sibling (Le Guen et al. 2013). Additionally, analysis of these patient's primary fibroblasts demonstrated shorter telomeres and genome instability (Le Guen et al. 2013). -

Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2019

This sequence change replaces cysteine with arginine at codon 1244 of the RTEL1 protein (p.Cys1244Arg). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs587777037, ExAC 0.003%). This variant has been observed to segregate with Hoyeraal–Hreidarsson syndrome in a family (PMID: 23591994). This variant has also been observed in an individual with aplastic anemia (PMID: 30995915). ClinVar contains an entry for this variant (Variation ID: 65412). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	21
DANN	Benign	0.96
Eigen	Benign	0.047
Eigen_PC	Benign	-0.099
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.20	D
MutationTaster	Benign	1.0	D;D;N;N;N
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.55		Gain of disorder (P = 0.0775);
MVP		0.86
ClinPred		0.87	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587777037; hg19: chr20-62326911;