20-63694486-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001283009.2(RTEL1):c.3107C>G(p.Thr1036Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000414 in 1,594,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1036K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

RTEL1
NM_001283009.2 missense, splice_region

Scores

Splicing: ADA: 0.00003521

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.00900

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028148651).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2 link	c.3107C>G	p.Thr1036Arg	missense_variant, splice_region_variant	Exon 31 of 35	ENST00000360203.11	NP_001269938.1	Q9NZ71-6R4IXY3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RTEL1	ENST00000360203.11 link	c.3107C>G	p.Thr1036Arg	missense_variant, splice_region_variant	Exon 31 of 35	5	NM_001283009.2	ENSP00000353332.5	Q9NZ71-6
RTEL1	ENST00000508582.7 link	c.3179C>G	p.Thr1060Arg	missense_variant, splice_region_variant	Exon 31 of 35	2		ENSP00000424307.2	Q9NZ71-7
RTEL1	ENST00000370018.7 link	c.3107C>G	p.Thr1036Arg	missense_variant, splice_region_variant	Exon 31 of 35	1		ENSP00000359035.3	Q9NZ71-1
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.*709C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 28 of 35	5		ENSP00000457428.1	D6RA96
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.*709C>G		3_prime_UTR_variant	Exon 28 of 35	5		ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000821

AC:

AN:

243572

AF XY:

0.0000528

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00156

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000185

Gnomad OTH exome

AF:

0.000502

GnomAD4 exome

AF:

0.0000381

AC:

AN:

1441992

Hom.:

Cov.:

AF XY:

0.0000350

AC XY:

AN XY:

714238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33128

American (AMR)

AF:

0.00

AC:

AN:

44072

Ashkenazi Jewish (ASJ)

AF:

0.00159

AC:

AN:

25772

East Asian (EAS)

AF:

0.00

AC:

AN:

39202

South Asian (SAS)

AF:

0.00

AC:

AN:

85604

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51884

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00000456

AC:

AN:

1097140

Other (OTH)

AF:

0.000151

AC:

AN:

59490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000226

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000351

AC:

ExAC

AF:

0.0000500

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 13, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge -

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

Uncertain:1

Sep 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 1036 of the RTEL1 protein (p.Thr1036Arg). This variant is present in population databases (rs138576158, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with RTEL1-related conditions. This variant is also known as NM_032957.4:c.3179C>G (p.Thr1060Arg). ClinVar contains an entry for this variant (Variation ID: 572880). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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:1

Aug 19, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.12

T;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.67

T;T;T;T

M_CAP

Benign

0.083

MetaRNN

Benign

0.028

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.1

L;.;L;.

PhyloP100

-0.0090

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.53

N;N;N;.

REVEL

Benign

0.27

Sift

Benign

0.46

T;T;T;.

Sift4G

Benign

0.47

T;T;T;T

Polyphen

0.0050

B;B;B;.

Vest4

0.21

MVP

0.74

ClinPred

0.018

GERP RS

-1.4

Varity_R

0.045

gMVP

0.25

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000035

dbscSNV1_RF

Benign

0.014

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.34

Position offset: 39

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over