20-63693189-G-C

Position:

chr20-63693189-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001283009.2(RTEL1):c.2898G>C(p.Glu966Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000988 in 1,612,174 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E966E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0053 ( 7 hom., cov: 33)

Exomes 𝑓: 0.00054 ( 5 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.660

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:

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 (MetaRNN=0.0036059618).

BP6

Variant 20-63693189-G-C is Benign according to our data. Variant chr20-63693189-G-C is described in ClinVar as [Benign]. Clinvar id is 436574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63693189-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00528 (804/152188) while in subpopulation AFR AF= 0.0185 (766/41504). AF 95% confidence interval is 0.0174. There are 7 homozygotes in gnomad4. There are 373 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2 linkuse as main transcript	c.2898G>C	p.Glu966Asp	missense_variant	30/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1 linkuse as main transcript	n.3725G>C		non_coding_transcript_exon_variant	30/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11 linkuse as main transcript	c.2898G>C	p.Glu966Asp	missense_variant	30/35	5	NM_001283009.2	A2	Q9NZ71-6

Frequencies

GnomAD3 genomes

AF:

0.00527

AC:

801

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0184

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00142

AC:

355

AN:

249374

Hom.:

AF XY:

0.000938

AC XY:

127

AN XY:

135378

show subpopulations

Gnomad AFR exome

AF:

0.0201

Gnomad AMR exome

AF:

0.000695

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000446

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000540

AC:

789

AN:

1459986

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

332

AN XY:

726290

show subpopulations

Gnomad4 AFR exome

AF:

0.0199

Gnomad4 AMR exome

AF:

0.000716

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.000895

GnomAD4 genome

AF:

0.00528

AC:

804

AN:

152188

Hom.:

Cov.:

AF XY:

0.00501

AC XY:

373

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0185

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000518

Hom.:

Bravo

AF:

0.00604

ESP6500AA

AF:

0.0198

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00170

AC:

205

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 09, 2018

- -

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 29, 2024

- -

Dyskeratosis congenita

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

3.4

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

T;.;.;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.67

T;T;T;T

MetaRNN

Benign

0.0036

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.10

N;.;N;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.4

N;N;N;.

REVEL

Benign

0.091

Sift

Benign

0.50

T;T;T;.

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.0050

B;B;B;.

Vest4

0.33

MutPred

0.30

Gain of sheet (P = 0.0477);.;Gain of sheet (P = 0.0477);.;

MVP

0.34

ClinPred

0.013

GERP RS

-0.23

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.057

gMVP

0.32

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

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