rs141522376

Positions:

• chr20-63695773-C-G
• chr20-63695773-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001283009.2(RTEL1):​c.3823-5C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,590,056 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (16 hom.)
• Consequence: RTEL1 NM_001283009.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001674
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0460

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 20-63695773-C-G is Benign according to our data. Variant chr20-63695773-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 436581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63695773-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00232 (353/152318) while in subpopulation NFE AF= 0.00387 (263/68006). AF 95% confidence interval is 0.00348. There are 3 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.3823-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000360203.11	NP_001269938.1
RTEL1-TNFRSF6B	NR_037882.1	n.4650-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11	c.3823-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001283009.2	ENSP00000353332	A2

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 352 AN: 152200 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00387

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00271 AC: 563 AN: 207454 Hom.: 0 AF XY: 0.00272 AC XY: 306 AN XY: 112630

Gnomad AFR exome AF: 0.000614

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000631

Gnomad SAS exome AF: 0.0000366

Gnomad FIN exome AF: 0.00172

Gnomad NFE exome AF: 0.00484

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00410 AC: 5895 AN: 1437738 Hom.: 16 Cov.: 33 AF XY: 0.00397 AC XY: 2835 AN XY: 713382

Gnomad4 AFR exome AF: 0.000544

Gnomad4 AMR exome AF: 0.00227

Gnomad4 ASJ exome AF: 0.0000390

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.0000598

Gnomad4 FIN exome AF: 0.00157

Gnomad4 NFE exome AF: 0.00497

Gnomad4 OTH exome AF: 0.00375

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152318 Hom.: 3 Cov.: 33 AF XY: 0.00200 AC XY: 149 AN XY: 74484

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00387

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00273 Hom.: 1

Bravo AF: 0.00266

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	RTEL1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Aug 22, 2017	BS1, BS2; This alteration has an allele frequency that is greater than expected for the associated disease, and was seen in a healthy adult where full penetrance of the disorder is expected at an early age. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 13, 2017	- -

Dyskeratosis congenita Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 16, 2019	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 21, 2020	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.1
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0017
dbscSNV1_RF	Benign	0.096
SpliceAI score (max)		0.15		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: rs141522376; hg19: chr20-62327126;