rs6062495

chr20-63695134-C-Achr20-63695134-C-Gchr20-63695134-C-T

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.3412C>A(p.Arg1138=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00887 in 1,612,400 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1138R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0058 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0092 (83 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.801

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=-0.74).
• BP6: Variant 20-63695134-C-A is Benign according to our data. Variant chr20-63695134-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 473921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63695134-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.801 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00582 (886/152288) while in subpopulation SAS AF= 0.0116 (56/4828). AF 95% confidence interval is 0.00917. There are 4 homozygotes in gnomad4. There are 409 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2	c.3412C>A	p.Arg1138=	synonymous_variant	33/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1	n.4239C>A		non_coding_transcript_exon_variant	33/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.3412C>A	p.Arg1138=	synonymous_variant	33/35	5	NM_001283009.2	A2

Frequencies

GnomAD3 genomes AF: 0.00582 AC: 886 AN: 152170 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00953

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00726 AC: 1779 AN: 245096 Hom.: 8 AF XY: 0.00757 AC XY: 1012 AN XY: 133604

Gnomad AFR exome AF: 0.00145

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00115

Gnomad SAS exome AF: 0.00870

Gnomad FIN exome AF: 0.00598

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00399

GnomAD4 exome AF: 0.00919 AC: 13421 AN: 1460112 Hom.: 83 Cov.: 35 AF XY: 0.00902 AC XY: 6555 AN XY: 726348

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.000453

Gnomad4 SAS exome AF: 0.00834

Gnomad4 FIN exome AF: 0.00590

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.00759

GnomAD4 genome AF: 0.00582 AC: 886 AN: 152288 Hom.: 4 Cov.: 33 AF XY: 0.00549 AC XY: 409 AN XY: 74454

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.00499

Gnomad4 NFE AF: 0.00953

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00507 Hom.: 0

Bravo AF: 0.00531

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

RTEL1: BP4, BP7, BS1, BS2; RTEL1-TNFRSF6B: BS1, BS2 -

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

Feb 01, 2024

- -

Dyskeratosis congenita Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 13, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	1.2
Dann	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs6062495; hg19: chr20-62326487;