rs3848668

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001283009.2(RTEL1):c.371A>G(p.Asn124Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0731 in 1,613,524 control chromosomes in the GnomAD database, including 4,760 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N124D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.057 ( 343 hom., cov: 32)

Exomes 𝑓: 0.075 ( 4417 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.70

Publications

24 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025758743).

BP6

Variant 20-63661919-A-G is Benign according to our data. Variant chr20-63661919-A-G is described in ClinVar as Benign. ClinVar VariationId is 1169883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2 link	c.371A>G	p.Asn124Ser	missense_variant	Exon 4 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.371A>G	p.Asn124Ser	missense_variant	Exon 4 of 35	5	NM_001283009.2	ENSP00000353332.5	Q9NZ71-6
RTEL1	ENST00000508582.7 link	c.371A>G	p.Asn124Ser	missense_variant	Exon 4 of 35	2		ENSP00000424307.2	Q9NZ71-7
RTEL1	ENST00000370018.7 link	c.371A>G	p.Asn124Ser	missense_variant	Exon 4 of 35	1		ENSP00000359035.3	Q9NZ71-1
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.371A>G		non_coding_transcript_exon_variant	Exon 3 of 35	5		ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes

AF:

0.0575

AC:

8726

AN:

151878

Hom.:

344

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0156

Gnomad AMI

AF:

0.116

Gnomad AMR

AF:

0.0609

Gnomad ASJ

AF:

0.0464

Gnomad EAS

AF:

0.000972

Gnomad SAS

AF:

0.0469

Gnomad FIN

AF:

0.0655

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0858

Gnomad OTH

AF:

0.0565

GnomAD2 exomes

AF:

0.0616

AC:

15490

AN:

251396

AF XY:

0.0624

show subpopulations

Gnomad AFR exome

AF:

0.0134

Gnomad AMR exome

AF:

0.0645

Gnomad ASJ exome

AF:

0.0469

Gnomad EAS exome

AF:

0.00152

Gnomad FIN exome

AF:

0.0648

Gnomad NFE exome

AF:

0.0803

Gnomad OTH exome

AF:

0.0673

GnomAD4 exome

AF:

0.0748

AC:

109251

AN:

1461528

Hom.:

4417

Cov.:

AF XY:

0.0743

AC XY:

54030

AN XY:

727054

show subpopulations

African (AFR)

AF:

0.0130

AC:

436

AN:

33480

American (AMR)

AF:

0.0619

AC:

2767

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0469

AC:

1225

AN:

26136

East Asian (EAS)

AF:

0.000831

AC:

AN:

39692

South Asian (SAS)

AF:

0.0523

AC:

4514

AN:

86252

European-Finnish (FIN)

AF:

0.0669

AC:

3574

AN:

53386

Middle Eastern (MID)

AF:

0.0477

AC:

275

AN:

5768

European-Non Finnish (NFE)

AF:

0.0832

AC:

92519

AN:

1111708

Other (OTH)

AF:

0.0647

AC:

3908

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

4969

9938

14907

19876

24845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3356

6712

10068

13424

16780

<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:

0.0574

AC:

8719

AN:

151996

Hom.:

343

Cov.:

AF XY:

0.0568

AC XY:

4219

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.0155

AC:

643

AN:

41460

American (AMR)

AF:

0.0608

AC:

928

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0464

AC:

161

AN:

3468

East Asian (EAS)

AF:

0.000975

AC:

AN:

5130

South Asian (SAS)

AF:

0.0459

AC:

220

AN:

4796

European-Finnish (FIN)

AF:

0.0655

AC:

693

AN:

10586

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0858

AC:

5829

AN:

67972

Other (OTH)

AF:

0.0564

AC:

119

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

414

828

1243

1657

2071

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.0699

Hom.:

1062

Bravo

AF:

0.0538

TwinsUK

AF:

0.0882

AC:

327

ALSPAC

AF:

0.0789

AC:

304

ESP6500AA

AF:

0.0175

AC:

ESP6500EA

AF:

0.0828

AC:

712

ExAC

AF:

0.0613

AC:

7439

Asia WGS

AF:

0.0330

AC:

116

AN:

3478

EpiCase

AF:

0.0844

EpiControl

AF:

0.0784

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 06, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dyskeratosis congenita

Benign:1

Oct 25, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.042

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.60

CADD

Benign

5.4

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.18

T;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.85

T;T;T;D

MetaRNN

Benign

0.0026

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.24

N;N;N;.

PhyloP100

1.7

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.050

N;N;N;N

REVEL

Benign

0.068

Sift

Benign

0.79

T;T;T;T

Sift4G

Benign

0.75

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.019

ClinPred

0.0010

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.022

gMVP

0.17

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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