20-63692927-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.2775C>T(p.Ser925=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,612,652 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (90 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.53

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=-0.77).
• BP6: Variant 20-63692927-C-T is Benign according to our data. Variant chr20-63692927-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 436569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63692927-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00442 (673/152326) while in subpopulation AMR AF= 0.0341 (522/15296). AF 95% confidence interval is 0.0317. There are 17 homozygotes in gnomad4. There are 344 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2	c.2775C>T	p.Ser925=	synonymous_variant	29/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1	n.3602C>T		non_coding_transcript_exon_variant	29/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.2775C>T	p.Ser925=	synonymous_variant	29/35	5	NM_001283009.2	A2

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 666 AN: 152208 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0337

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.00351

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00835 AC: 2087 AN: 249842 Hom.: 62 AF XY: 0.00650 AC XY: 881 AN XY: 135614

Gnomad AFR exome AF: 0.000621

Gnomad AMR exome AF: 0.0514

Gnomad ASJ exome AF: 0.00400

Gnomad EAS exome AF: 0.00348

Gnomad SAS exome AF: 0.00245

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000774

Gnomad OTH exome AF: 0.00590

GnomAD4 exome AF: 0.00241 AC: 3519 AN: 1460326 Hom.: 90 Cov.: 31 AF XY: 0.00221 AC XY: 1603 AN XY: 726456

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.0504

Gnomad4 ASJ exome AF: 0.00348

Gnomad4 EAS exome AF: 0.00516

Gnomad4 SAS exome AF: 0.00226

Gnomad4 FIN exome AF: 0.0000384

Gnomad4 NFE exome AF: 0.000507

Gnomad4 OTH exome AF: 0.00265

GnomAD4 genome AF: 0.00442 AC: 673 AN: 152326 Hom.: 17 Cov.: 33 AF XY: 0.00462 AC XY: 344 AN XY: 74492

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.0341

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00405

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.00705

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000534

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 27, 2021

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 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

GeneDx

Apr 02, 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

Invitae

Jan 31, 2024

- -

RTEL1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2019

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

Dyskeratosis congenita Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.072
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs12480346; hg19: chr20-62324280; COSMIC: COSV58894644; COSMIC: COSV58894644;