rs181080831

chr20-63695521-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001283009.2(RTEL1):c.3693G>A(p.Thr1231=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,612,198 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (9 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.294

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 20-63695521-G-A is Benign according to our data. Variant chr20-63695521-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 436580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.294 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00265 (404/152332) while in subpopulation NFE AF= 0.00387 (263/68024). AF 95% confidence interval is 0.00348. There are 2 homozygotes in gnomad4. There are 187 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2	c.3693G>A	p.Thr1231=	synonymous_variant	34/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1	n.4520G>A		non_coding_transcript_exon_variant	34/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.3693G>A	p.Thr1231=	synonymous_variant	34/35	5	NM_001283009.2	A2

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 404 AN: 152214 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00387

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00259 AC: 638 AN: 246088 Hom.: 1 AF XY: 0.00278 AC XY: 374 AN XY: 134330

Gnomad AFR exome AF: 0.000389

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.00212

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00141

Gnomad FIN exome AF: 0.000374

Gnomad NFE exome AF: 0.00413

Gnomad OTH exome AF: 0.00366

GnomAD4 exome AF: 0.00321 AC: 4691 AN: 1459866 Hom.: 9 Cov.: 34 AF XY: 0.00318 AC XY: 2311 AN XY: 726240

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00269

Gnomad4 ASJ exome AF: 0.00234

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00142

Gnomad4 FIN exome AF: 0.000501

Gnomad4 NFE exome AF: 0.00372

Gnomad4 OTH exome AF: 0.00278

GnomAD4 genome AF: 0.00265 AC: 404 AN: 152332 Hom.: 2 Cov.: 33 AF XY: 0.00251 AC XY: 187 AN XY: 74486

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00387

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00285 Hom.: 1

Bravo AF: 0.00294

EpiCase AF: 0.00513

EpiControl AF: 0.00486

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RTEL1: BP4, BP7 -

Dyskeratosis congenita Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 25, 2019	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 10, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 19, 2021

- -

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

Invitae

Jan 31, 2024

- -

RTEL1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	8.4
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs181080831; hg19: chr20-62326874;