20-63693211-C-T

Position:

• chr20-63693211-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The ENST00000370018.7(RTEL1):​c.2920C>T​(p.Arg974*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000571 in 1,611,994 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R974R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: RTEL1 ENST00000370018.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 0.632

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]

RTEL1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 20-63693211-C-T is Pathogenic according to our data. Variant chr20-63693211-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 42020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63693211-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.2920C>T	p.Arg974*	stop_gained	30/35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11	c.2920C>T	p.Arg974*	stop_gained	30/35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7	c.2992C>T	p.Arg998*	stop_gained	30/35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7	c.2920C>T	p.Arg974*	stop_gained	30/35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6	n.*522C>T		non_coding_transcript_exon_variant	27/35	5		ENSP00000457428.1
RTEL1-TNFRSF6B	ENST00000492259.6	n.*522C>T		3_prime_UTR_variant	27/35	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152040 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 249302 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135350

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000625

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000555 AC: 81 AN: 1459954 Hom.: 0 Cov.: 33 AF XY: 0.0000661 AC XY: 48 AN XY: 726288

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152040 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74244

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000572 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dyskeratosis congenita, autosomal recessive 5 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 02, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 03, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000042020, PMID:23453664). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000032, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed stop gained c.2920C>T (p.Arg974Ter) variant in RTEL1 gene has been reported previously in multiple individuals affected with RTEL1-related disorders (Walne et al., 2013; Deng et al., 2013; Cogan et al., 2015; Ballew et al., 2013). It has also been observed to segregate with disease in related individuals. The functional study showed that Arg974Ter transcript was degraded by nonsense-mediated decay and cells with variant showed significantly shortening telomeres (Walne et al., 2013; Deng et al., 2013). The p.Arg974Ter variant is present with allele frequency of 0.003% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. The reference amino acid of p.Arg974Ter in RTEL1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in RTEL1 gene have been previously reported to be disease causing (Deng et al., 2013). For these reasons, this variant has been classified as Pathogenic. -

Dyskeratosis congenita Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 16, 2016	Variant summary: The RTEL1 c.2992C>T (p.Arg998X) variant results in a premature termination codon, predicted to cause a truncated or absent RTEL1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The functional study showed that R974X transcript was degraded by nonsense-mediated decay (Deng_2013), and cells with variant showed significantly shortening telomeres (Deng_2013, Walne_2013) compare to WT. One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/119914 control chromosomes at a frequency of 0.0000167, which does not exceed the estimated maximal expected allele frequency of a pathogenic RTEL1 variant (0.001118). This variant has been reported in multiple affected individuals with HHS and the variant was shown to co-segregate with disease in at least two families. In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 13, 2019	The p.Arg998X variant in RTEL1 has been reported in the compound heterozygous state in 3 individuals with dyskeratosis congenita or Hoyeraal-Hreidarsson syndrome (Walne 2013, Ballew 2013, Deng 2013) and segregated disease in 5 affected relatives from 2 families (Walne 2013, Deng 2013). It was also identified in the heterozygous state in 3 individuals with pulmonary fibrosis (Petrovski 2017). In vitro functional studies provide evidence that the p.Arg998X variant impacts protein function (Deng 2013). This variant has also been identified in 6/125600 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org)and reported in ClinVar (Variation ID #42020). This nonsense variant leads to a premature termination codon at position 998 which is predicted to lead to a truncated or absent protein. Loss of function of the RTEL1 gene is an established disease mechanism in autosomal recessive dyskeratosis congenita. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive dyskeratosis congenita. ACMG/AMP Criteria applied: PVS1, PM2, PM3_Strong, PS3_Supporting, PP1_Strong. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	RTEL1: PVS1, PM2, PS4:Moderate, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2024	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect on telomere function, structure, and length (PMID: 23959892); Also known as c.2920C>T p.(R974*); This variant is associated with the following publications: (PMID: 23453664, 23329068, 30995915, 25607374, 23959892, 29344583, 33718801, 36090019, 28099038, 25047097, 37354000, 36845387, 36655009) -

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

- -

Pulmonary fibrosis Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center

Jun 09, 2022

Pathogenic criteria: null variant (PVS1) with functional study supportive of damaging effect (PS3): leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted -

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

Pathogenic, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Nov 29, 2023

This RTEL1 variant has been reported in the literature in individuals with autosomal dominant as well as recessive RTEL1-related disorders. It (rs398123017) has been reported in ClinVar (Variation ID 42020), and is rare (<0.1%) in a large population dataset (gnomAD v4.0.0: 92/1611994 total alleles; 0.006%; no homozygotes). This nonsense variant results in a premature stop codon in exon 30 of 35, likely leading to nonsense-mediated decay and lack of protein production, which is supported by a functional study. We consider c.2920C>T in RTEL1 to be pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change creates a premature translational stop signal (p.Arg974*) in the RTEL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RTEL1 are known to be pathogenic (PMID: 23453664, 23959892, 25607374). This variant is present in population databases (rs398123017, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with dyskeratosis congenita, familial interstitial pneumonia, and/or idiopathic pulmonary fibrosis (PMID: 23329068, 23959892, 25607374, 28099038). It has also been observed to segregate with disease in related individuals. This variant is also known as R974X. ClinVar contains an entry for this variant (Variation ID: 42020). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.41	N
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.77
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs398123017; hg19: chr20-62324564;