rs143550996

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001283009.2(RTEL1):c.959T>C(p.Met320Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,612,424 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M320V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0016 ( 4 hom. )

Consequence

RTEL1
NM_001283009.2 missense, splice_region

Scores

Splicing: ADA: 0.0001307

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 0.568

Publications

4 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:

LOC124904954 (HGNC:):

LOC124904954 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013461858).

BP6

Variant 20-63678268-T-C is Benign according to our data. Variant chr20-63678268-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540945.

BS2

High Homozygotes in GnomAdExome4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2 link	c.959T>C	p.Met320Thr	missense_variant, splice_region_variant	Exon 12 of 35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RTEL1	ENST00000360203.11 link	c.959T>C	p.Met320Thr	missense_variant, splice_region_variant	Exon 12 of 35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7 link	c.1031T>C	p.Met344Thr	missense_variant, splice_region_variant	Exon 12 of 35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7 link	c.959T>C	p.Met320Thr	missense_variant, splice_region_variant	Exon 12 of 35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.1043T>C		non_coding_transcript_exon_variant	Exon 10 of 35	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes

AF:

0.00107

AC:

163

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00169

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.00112

AC:

279

AN:

249962

AF XY:

0.00113

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.0000999

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00229

Gnomad NFE exome

AF:

0.00175

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.00159

AC:

2317

AN:

1460264

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

1115

AN XY:

726126

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33468

American (AMR)

AF:

0.000224

AC:

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.000371

AC:

AN:

86158

European-Finnish (FIN)

AF:

0.00261

AC:

139

AN:

53240

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00184

AC:

2047

AN:

1110944

Other (OTH)

AF:

0.00123

AC:

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

125

250

374

499

624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<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:

0.00107

AC:

163

AN:

152160

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41540

American (AMR)

AF:

0.000785

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000416

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00169

AC:

115

AN:

67972

Other (OTH)

AF:

0.000950

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00109

Hom.:

Bravo

AF:

0.000907

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00107

AC:

130

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Mar 02, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in two individuals with suspected familial bone marrow failure, one with shortened telomeres that also carried a variant in TERT, and another with normal telomere length (Marsh 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as M320T (c.959T>C); This variant is associated with the following publications: (PMID: 29344583) -

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dyskeratosis congenita

Uncertain:1Benign:1

Sep 23, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Sep 16, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Uncertain:1

May 18, 2022

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

DNA sequence analysis of the RTEL1 gene demonstrated a sequence change, c.1031T>C, in exon 12 that results in an amino acid change, p.Met344Thr (cDNA transcript used: NM_032957.4). This sequence change has been described in the gnomAD database with a frequency of 0.22% in the European Finnish subpopulation (dbSNP rs143550996). The p.Met344Thr change affects a poorly conserved amino acid residue located in a domain of the RTEL1 protein that is known to be functional. The p.Met344Thr substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with RTEL1-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Met344Thr change remains unknown at this time. -

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

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

6.7

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.12

T;.;.;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.56

T;T;T;T

M_CAP

Benign

0.057

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.2

L;.;L;.

PhyloP100

0.57

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.93

N;N;N;.

REVEL

Benign

0.20

Sift

Benign

0.54

T;T;T;.

Sift4G

Benign

0.56

T;T;T;T

Polyphen

0.0060

B;B;B;.

Vest4

0.33

MVP

0.35

ClinPred

0.0069

GERP RS

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.020

gMVP

0.25

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00013

dbscSNV1_RF

Benign

0.0060

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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