20-63678326-C-T

Position:

chr20-63678326-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001283009.2(RTEL1):c.1017C>T(p.Ser339=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,612,540 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0058 ( 33 hom. )

Consequence

RTEL1
NM_001283009.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.884

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:):

RTEL1-TNFRSF6B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 20-63678326-C-T is Benign according to our data. Variant chr20-63678326-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 473901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63678326-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.884 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00343 (522/152240) while in subpopulation NFE AF= 0.00638 (434/68016). AF 95% confidence interval is 0.00589. There are 1 homozygotes in gnomad4. There are 215 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 33 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RTEL1	NM_001283009.2 linkuse as main transcript	c.1017C>T	p.Ser339=	synonymous_variant	12/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1 linkuse as main transcript	n.1844C>T		non_coding_transcript_exon_variant	12/38
LOC124904954	XR_007067717.1 linkuse as main transcript	n.50G>A		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11 linkuse as main transcript	c.1017C>T	p.Ser339=	synonymous_variant	12/35	5	NM_001283009.2	A2	Q9NZ71-6

Frequencies

GnomAD3 genomes

AF:

0.00343

AC:

522

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00638

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00353

AC:

874

AN:

247720

Hom.:

AF XY:

0.00365

AC XY:

491

AN XY:

134358

show subpopulations

Gnomad AFR exome

AF:

0.000496

Gnomad AMR exome

AF:

0.00227

Gnomad ASJ exome

AF:

0.000803

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000623

Gnomad FIN exome

AF:

0.000782

Gnomad NFE exome

AF:

0.00638

Gnomad OTH exome

AF:

0.00513

GnomAD4 exome

AF:

0.00578

AC:

8438

AN:

1460300

Hom.:

Cov.:

AF XY:

0.00566

AC XY:

4114

AN XY:

726434

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00226

Gnomad4 ASJ exome

AF:

0.000919

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000882

Gnomad4 FIN exome

AF:

0.00101

Gnomad4 NFE exome

AF:

0.00707

Gnomad4 OTH exome

AF:

0.00487

GnomAD4 genome

AF:

0.00343

AC:

522

AN:

152240

Hom.:

Cov.:

AF XY:

0.00289

AC XY:

215

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.00638

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00400

Hom.:

Bravo

AF:

0.00345

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00562

EpiControl

AF:

0.00682

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	RTEL1: BP4, BP7, BS2 -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 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. -

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

Jan 31, 2024

- -

Dyskeratosis congenita

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Feb 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.061

DANN

Benign

0.72

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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