rs41309931

Variant names:

• chr20-63695226-G-T
• rs41309931
• NM_001283009.2:c.3499+5G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001283009.2(RTEL1):​c.3499+5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,610,464 control chromosomes in the GnomAD database, including 14,426 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1207 hom., cov: 32)
  • Exomes 𝑓: 0.12 (13219 hom.)
• Consequence: RTEL1 NM_001283009.2 splice_region, intron
• Scores: Splicing: ADA: 0.9398
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 1.33
• Publications: 20 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 20-63695226-G-T is Benign according to our data. Variant chr20-63695226-G-T is described in ClinVar as Benign. ClinVar VariationId is 403403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.3499+5G>T		splice_region_variant, intron_variant	Intron 33 of 34	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11	c.3499+5G>T		splice_region_variant, intron_variant	Intron 33 of 34	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7	c.3571+5G>T		splice_region_variant, intron_variant	Intron 33 of 34	2		ENSP00000424307.2
RTEL1	ENST00000370018.7	c.3499+5G>T		splice_region_variant, intron_variant	Intron 33 of 34	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6	n.*1101+5G>T		splice_region_variant, intron_variant	Intron 30 of 34	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15817 AN: 151970 Hom.: 1202 Cov.: 32

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.0821

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0749

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.149 AC: 36332 AN: 244330 AF XY: 0.141

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.365

Gnomad ASJ exome AF: 0.0847

Gnomad EAS exome AF: 0.220

Gnomad FIN exome AF: 0.0814

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.124 AC: 181111 AN: 1458376 Hom.: 13219 Cov.: 35 AF XY: 0.122 AC XY: 88833 AN XY: 725286

African (AFR) AF: 0.0229 AC: 765 AN: 33446

American (AMR) AF: 0.350 AC: 15625 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.0848 AC: 2211 AN: 26066

East Asian (EAS) AF: 0.230 AC: 9119 AN: 39648

South Asian (SAS) AF: 0.109 AC: 9387 AN: 86196

European-Finnish (FIN) AF: 0.0869 AC: 4478 AN: 51558

Middle Eastern (MID) AF: 0.101 AC: 581 AN: 5758

European-Non Finnish (NFE) AF: 0.118 AC: 131365 AN: 1110764

Other (OTH) AF: 0.126 AC: 7580 AN: 60284

GnomAD4 genome AF: 0.104 AC: 15838 AN: 152088 Hom.: 1207 Cov.: 32 AF XY: 0.105 AC XY: 7776 AN XY: 74330

African (AFR) AF: 0.0281 AC: 1166 AN: 41520

American (AMR) AF: 0.234 AC: 3583 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0821 AC: 285 AN: 3472

East Asian (EAS) AF: 0.232 AC: 1192 AN: 5142

South Asian (SAS) AF: 0.108 AC: 520 AN: 4816

European-Finnish (FIN) AF: 0.0749 AC: 794 AN: 10606

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7909 AN: 67930

Other (OTH) AF: 0.132 AC: 278 AN: 2112

Alfa AF: 0.125 Hom.: 674

Bravo AF: 0.116

Asia WGS AF: 0.176 AC: 612 AN: 3478

EpiCase AF: 0.120

EpiControl AF: 0.116

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 43% of patients studied by a panel of primary immunodeficiencies. Number of patients: 41. Only high quality variants are reported. -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Dyskeratosis congenita, autosomal recessive 5 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dyskeratosis congenita Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	17
DANN	Benign	0.82
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.67
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41309931; hg19: chr20-62326579; COSMIC: COSV53926756; COSMIC: COSV53926756;