rs76364377

Positions:

chr20-63687931-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001283009.2(RTEL1):c.1482-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0624 in 1,612,066 control chromosomes in the GnomAD database, including 3,568 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 0.046 ( 244 hom., cov: 33)

Exomes 𝑓: 0.064 ( 3324 hom. )

Consequence

RTEL1
NM_001283009.2 splice_region, intron

Scores

Splicing: ADA: 0.0001018

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.05

Variant links:

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 links:

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]

RTEL1-TNFRSF6B links:

RTEL1-TNFRSF6B (HGNC:):

RTEL1-TNFRSF6B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 20-63687931-G-A is Benign according to our data. Variant chr20-63687931-G-A is described in ClinVar as [Benign]. Clinvar id is 473905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63687931-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTEL1	NM_001283009.2 linkuse as main transcript	c.1482-6G>A		splice_region_variant, intron_variant		ENST00000360203.11	NP_001269938.1	Q9NZ71-6R4IXY3

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
RTEL1	ENST00000360203.11 linkuse as main transcript	c.1482-6G>A	splice_region_variant, intron_variant	5	NM_001283009.2	ENSP00000353332.5	Q9NZ71-6
RTEL1	ENST00000508582.7 linkuse as main transcript	c.1554-6G>A	splice_region_variant, intron_variant	2		ENSP00000424307.2	Q9NZ71-7
RTEL1	ENST00000370018.7 linkuse as main transcript	c.1482-6G>A	splice_region_variant, intron_variant	1		ENSP00000359035.3	Q9NZ71-1
RTEL1-TNFRSF6B	ENST00000492259.6 linkuse as main transcript	n.1566-6G>A	splice_region_variant, intron_variant	5		ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes

AF:

0.0464

AC:

7057

AN:

152148

Hom.:

244

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0128

Gnomad AMI

AF:

0.0866

Gnomad AMR

AF:

0.0407

Gnomad ASJ

AF:

0.0207

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0445

Gnomad FIN

AF:

0.0440

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0732

Gnomad OTH

AF:

0.0430

GnomAD3 exomes

AF:

0.0474

AC:

11804

AN:

248810

Hom.:

385

AF XY:

0.0486

AC XY:

6573

AN XY:

135332

show subpopulations

Gnomad AFR exome

AF:

0.0111

Gnomad AMR exome

AF:

0.0283

Gnomad ASJ exome

AF:

0.0206

Gnomad EAS exome

AF:

0.000708

Gnomad SAS exome

AF:

0.0502

Gnomad FIN exome

AF:

0.0472

Gnomad NFE exome

AF:

0.0676

Gnomad OTH exome

AF:

0.0539

GnomAD4 exome

AF:

0.0641

AC:

93508

AN:

1459800

Hom.:

3324

Cov.:

AF XY:

0.0637

AC XY:

46281

AN XY:

726186

show subpopulations

Gnomad4 AFR exome

AF:

0.0105

Gnomad4 AMR exome

AF:

0.0287

Gnomad4 ASJ exome

AF:

0.0209

Gnomad4 EAS exome

AF:

0.000504

Gnomad4 SAS exome

AF:

0.0494

Gnomad4 FIN exome

AF:

0.0514

Gnomad4 NFE exome

AF:

0.0729

Gnomad4 OTH exome

AF:

0.0538

GnomAD4 genome

AF:

0.0463

AC:

7050

AN:

152266

Hom.:

244

Cov.:

AF XY:

0.0454

AC XY:

3384

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0127

Gnomad4 AMR

AF:

0.0406

Gnomad4 ASJ

AF:

0.0207

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.0439

Gnomad4 FIN

AF:

0.0440

Gnomad4 NFE

AF:

0.0732

Gnomad4 OTH

AF:

0.0421

Alfa

AF:

0.0586

Hom.:

149

Bravo

AF:

0.0421

Asia WGS

AF:

0.0290

AC:

AN:

3478

EpiCase

AF:

0.0682

EpiControl

AF:

0.0629

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 01, 2018	c.1554-6G>A in intron 17 of RTEL1: This variant is not expected to have clinical significance because it has been identified in 7% (8722/125530) of European chr omosomes by the Genome Aggregation Databse (gnomAD, http://exac.broadinstitute.o rg; dbSNP rs76364377). ACMG/AMP Criteria applied: BA1; BP4. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2019	- -

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

Feb 01, 2024

- -

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

-0.80

CADD

Benign

1.1

DANN

Benign

0.50

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00010

dbscSNV1_RF

Benign

0.048

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over