20-63689578-T-C

Position:

chr20-63689578-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001283009.2(RTEL1):c.1955T>C(p.Met652Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000494 in 1,612,198 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00051 ( 1 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 1.70

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13863885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTEL1	NM_001283009.2 linkuse as main transcript	c.1955T>C	p.Met652Thr	missense_variant	23/35	ENST00000360203.11	NP_001269938.1	Q9NZ71-6R4IXY3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RTEL1	ENST00000360203.11 linkuse as main transcript	c.1955T>C	p.Met652Thr	missense_variant	23/35	5	NM_001283009.2	ENSP00000353332.5	Q9NZ71-6
RTEL1	ENST00000508582.7 linkuse as main transcript	c.2027T>C	p.Met676Thr	missense_variant	23/35	2		ENSP00000424307.2	Q9NZ71-7
RTEL1	ENST00000370018.7 linkuse as main transcript	c.1955T>C	p.Met652Thr	missense_variant	23/35	1		ENSP00000359035.3	Q9NZ71-1
RTEL1-TNFRSF6B	ENST00000492259.6 linkuse as main transcript	n.2039T>C		non_coding_transcript_exon_variant	21/35	5		ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000242

AC:

AN:

248424

Hom.:

AF XY:

0.000274

AC XY:

AN XY:

134836

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.000483

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000512

AC:

747

AN:

1460082

Hom.:

Cov.:

AF XY:

0.000516

AC XY:

375

AN XY:

726320

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000230

Gnomad4 NFE exome

AF:

0.000634

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000329

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000573

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000413

Hom.:

Bravo

AF:

0.000283

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000141

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2018	The p.Met676Thr variant in RTEL1 has not been previously reported in individuals with pulmonary fibrosis or dyskeratosis congenita, but has been identified in 0 .05% (62/125316) of European American chromosomes by the Genome Aggregation Data base (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148080505). Although the variant was observed in the general population, its frequency is not high enoug h to rule out pathogenicity. The variant has also been reported in ClinVar (Vari ation ID:436587). Computational prediction tools and conservation analysis do no t provide strong support for or against an impact to the protein. In summary, th e clinical significance of the p.Met676Thr variant is uncertain. ACMG/AMP Criter ia applied: none. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 24, 2015	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies do not demonstrate a conclusive damaging effect (PMID: 29344583); Also known as c.1955T>C p.M652T; This variant is associated with the following publications: (PMID: 29344583, 30523342) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 19, 2023	- -

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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 03, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 652 of the RTEL1 protein (p.Met652Thr). This variant is present in population databases (rs148080505, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of RTEL1-related conditions (PMID: 30523342). ClinVar contains an entry for this variant (Variation ID: 436587). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect RTEL1 function (PMID: 29344583). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Dyskeratosis congenita

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 20, 2020	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 03, 2021	- -

Dyskeratosis congenita, autosomal recessive 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Uncertain

0.78

D;.;.;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.73

T;T;T;T

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-0.31

MutationAssessor

Benign

0.81

L;.;L;.

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.4

D;D;D;.

REVEL

Uncertain

0.42

Sift

Benign

0.12

T;T;T;.

Sift4G

Benign

0.35

T;T;T;T

Polyphen

0.10

B;P;B;.

Vest4

0.31

MVP

0.70

ClinPred

0.078

GERP RS

2.3

Varity_R

0.21

gMVP

0.63

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