rs201540674

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PS3PP5_Very_StrongBP4

The NM_001283009.2(RTEL1):c.3791G>A(p.Arg1264His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000782 in 1,611,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000617167: Published functional studies demonstrate a significant increase in telomere loss and increase in cells with telomere dysfunction-induced foci (Sarek et al., 2015)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1264C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17O:1

Conservation

PhyloP100: 1.50

Publications

26 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

new If you want to explore the variant's impact on the transcript NM_001283009.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000617167: Published functional studies demonstrate a significant increase in telomere loss and increase in cells with telomere dysfunction-induced foci (Sarek et al., 2015);; SCV000699754: The most pronounced variant effect results in telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C (Ballew_2013).; SCV001365991: in vitro functional studies suggest that this variant impacts protein function (Sarek 2015).; SCV000954851: Experimental studies have shown that this missense change affects RTEL1 function (PMID: 24009516, 25620558).; SCV003714967: Patient-derived cell lines demonstrated deficient function as indicated by telomere length heterogeneity, the presence of extra-chromosomal circular telomeric DNA, hypersensitivity to DNA damage and increased sister chromatid exchange (Ballew, 2013). In addition, both patient-derived cells and mutant mouse embryonic fibroblasts demonstrated compromised RTEL1-TRF2 interaction leading to accumulation of telomere circles and telomere loss (Sarek, 2015).

PP5

Variant 20-63695619-G-A is Pathogenic according to our data. Variant chr20-63695619-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 42018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.08357221). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001283009.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RTEL1	NM_001283009.2	MANE Select	c.3791G>A	p.Arg1264His	missense	Exon 34 of 35	NP_001269938.1	Q9NZ71-6
RTEL1	NM_032957.5		c.3724+139G>A		intron	N/A	NP_116575.3	Q9NZ71-7
RTEL1	NM_016434.4		c.3652+139G>A		intron	N/A	NP_057518.1	Q9NZ71-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.3791G>A	p.Arg1264His	missense	Exon 34 of 35	ENSP00000353332.5	Q9NZ71-6
RTEL1	ENST00000508582.7	TSL:2	c.3724+139G>A		intron	N/A	ENSP00000424307.2	Q9NZ71-7
RTEL1	ENST00000370018.7	TSL:1	c.3652+139G>A		intron	N/A	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000158

AC:

AN:

247320

AF XY:

0.000178

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00342

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000449

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000788

AC:

115

AN:

1459298

Hom.:

Cov.:

AF XY:

0.0000813

AC XY:

AN XY:

726002

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00325

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51068

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1111872

Other (OTH)

AF:

0.000182

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

152204

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.00160

Hom.:

Bravo

AF:

0.000117

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (4)

Dyskeratosis congenita (3)

Dyskeratosis congenita, autosomal recessive 5 (4)

not provided (3)

Inborn genetic diseases (1)

Interstitial lung disease 2 (1)

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.88

MetaRNN

Benign

0.084

MetaSVM

Uncertain

-0.19

PhyloP100

1.5

PROVEAN

Benign

-0.88

REVEL

Uncertain

0.64

Sift

Uncertain

0.011

Sift4G

Benign

0.12

gMVP

0.40

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over