20-63692937-G-A

Position:

chr20-63692937-G-A

Variant summary

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

The NM_001283009.2(RTEL1):c.2785G>A(p.Ala929Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0333 in 1,612,586 control chromosomes in the GnomAD database, including 1,007 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A929A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.026 ( 57 hom., cov: 33)

Exomes 𝑓: 0.034 ( 950 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.375

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=0.002790749).

BP6

Variant 20-63692937-G-A is Benign according to our data. Variant chr20-63692937-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 473914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63692937-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.026 (3956/152306) while in subpopulation NFE AF= 0.0376 (2558/68004). AF 95% confidence interval is 0.0364. There are 57 homozygotes in gnomad4. There are 1883 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 57 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2 linkuse as main transcript	c.2785G>A	p.Ala929Thr	missense_variant	29/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1 linkuse as main transcript	n.3612G>A		non_coding_transcript_exon_variant	29/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11 linkuse as main transcript	c.2785G>A	p.Ala929Thr	missense_variant	29/35	5	NM_001283009.2	A2	Q9NZ71-6

Frequencies

GnomAD3 genomes

AF:

0.0260

AC:

3956

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00828

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.0286

Gnomad ASJ

AF:

0.0265

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00951

Gnomad FIN

AF:

0.0360

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0376

Gnomad OTH

AF:

0.0258

GnomAD3 exomes

AF:

0.0274

AC:

6839

AN:

249762

Hom.:

118

AF XY:

0.0284

AC XY:

3846

AN XY:

135584

show subpopulations

Gnomad AFR exome

AF:

0.00696

Gnomad AMR exome

AF:

0.0189

Gnomad ASJ exome

AF:

0.0249

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0128

Gnomad FIN exome

AF:

0.0378

Gnomad NFE exome

AF:

0.0394

Gnomad OTH exome

AF:

0.0302

GnomAD4 exome

AF:

0.0341

AC:

49732

AN:

1460280

Hom.:

950

Cov.:

AF XY:

0.0339

AC XY:

24660

AN XY:

726438

show subpopulations

Gnomad4 AFR exome

AF:

0.00606

Gnomad4 AMR exome

AF:

0.0201

Gnomad4 ASJ exome

AF:

0.0255

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0130

Gnomad4 FIN exome

AF:

0.0378

Gnomad4 NFE exome

AF:

0.0386

Gnomad4 OTH exome

AF:

0.0315

GnomAD4 genome

AF:

0.0260

AC:

3956

AN:

152306

Hom.:

Cov.:

AF XY:

0.0253

AC XY:

1883

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00828

Gnomad4 AMR

AF:

0.0286

Gnomad4 ASJ

AF:

0.0265

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00952

Gnomad4 FIN

AF:

0.0360

Gnomad4 NFE

AF:

0.0376

Gnomad4 OTH

AF:

0.0255

Alfa

AF:

0.0318

Hom.:

Bravo

AF:

0.0252

TwinsUK

AF:

0.0396

AC:

147

ALSPAC

AF:

0.0418

AC:

161

ESP6500AA

AF:

0.0107

AC:

ESP6500EA

AF:

0.0370

AC:

318

ExAC

AF:

0.0271

AC:

3273

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0375

EpiControl

AF:

0.0419

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2022	See Variant Classification Assertion Criteria. -

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, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.80

CADD

Benign

3.1

DANN

Benign

0.89

DEOGEN2

Benign

0.10

T;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.54

T;T;T;T

MetaRNN

Benign

0.0028

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.;L;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.30

N;N;N;.

REVEL

Benign

0.023

Sift

Benign

0.095

T;T;T;.

Sift4G

Benign

0.25

T;T;T;T

Polyphen

0.21

B;P;P;.

Vest4

0.076

ClinPred

0.0023

GERP RS

-5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.16

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

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