rs370343781

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_001283009.2(RTEL1):c.1476G>T(p.Met492Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 1,572,500 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 9.46

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 made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PP5

Variant 20-63687765-G-T is Pathogenic according to our data. Variant chr20-63687765-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2 link	c.1476G>T	p.Met492Ile	missense_variant	Exon 17 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.1476G>T	p.Met492Ile	missense_variant	Exon 17 of 35	5	NM_001283009.2	ENSP00000353332.5	Q9NZ71-6
RTEL1	ENST00000508582.7 link	c.1548G>T	p.Met516Ile	missense_variant	Exon 17 of 35	2		ENSP00000424307.2	Q9NZ71-7
RTEL1	ENST00000370018.7 link	c.1476G>T	p.Met492Ile	missense_variant	Exon 17 of 35	1		ENSP00000359035.3	Q9NZ71-1
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.1560G>T		non_coding_transcript_exon_variant	Exon 15 of 35	5		ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

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

GnomAD3 exomes

AF:

0.0000488

AC:

AN:

184516

Hom.:

AF XY:

0.0000605

AC XY:

AN XY:

99110

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000912

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000205

GnomAD4 exome

AF:

0.0000211

AC:

AN:

1420236

Hom.:

Cov.:

AF XY:

0.0000213

AC XY:

AN XY:

703182

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000946

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000183

Gnomad4 OTH exome

AF:

0.0000682

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000557

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000168

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dyskeratosis congenita, autosomal recessive 5

Pathogenic:2

Mar 21, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 03, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:2

Nov 10, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate telomere shortening, fragility and fusion, and growth defects (PMID: 23959892); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as M492I; This variant is associated with the following publications: (PMID: 23453664, 27418648, 27415407, 19461895, 25047097, 23959892, 32561545, 32542379, 25940403) -

Mar 10, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Apr 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 492 of the RTEL1 protein (p.Met492Ile). This variant is present in population databases (rs370343781, gnomAD 0.09%). This missense change has been observed in individual(s) with Hoyeraal‚Äö√Ñ√¨Hreidarsson syndrome and myelodysplastic syndrome (PMID: 19461895, 23453664, 23959892, 27418648). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.1548G>T (p.Met516Ile). ClinVar contains an entry for this variant (Variation ID: 42019). 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 disruptive. Experimental studies have shown that this missense change affects RTEL1 function (PMID: 19461895, 23959892). This variant disrupts the p.Met492 amino acid residue in RTEL1. Other variant(s) that disrupt this residue have been observed in individuals with RTEL1-related conditions (PMID: 26808564), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Dyskeratosis congenita

Pathogenic:1

Jun 16, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The RTEL1 c.1548G>T (p.Met516Ile) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools used predict a damaging outcome. This variant was found in 2/35814 control chromosomes at a frequency of 0.0000558, which does not exceed the estimated maximal expected allele frequency of a pathogenic RTEL1 variant (0.001118). This variant has been detected in four affected siblings from a family who were compound heterozygous for this variant and R998X. The parents were carriers of either of the mutations and an unaffected grandfather carried this variant in heterozygous state. This family data is consistent with disease causing outcome of the variant. Functional studies using patient cells showed telomere shortening, increased senescence, and an increased frequency of telomere defects, such as fragile telomeres and signal-free ends, but no increase in pathogenic T-circle formation on 2D gel electrophoresis (Deng_2013). The same authors also showed minor changes in telomere length caused by the variant in vitro. Jalas (2013) reports the carrier frequency of this variant in AJ as 0.19%. Two reputable databases have classified this variant as pathogenic. Taken together, this variant is currently classified as a Probable Disease Variant (or Likely Pathogenic). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.;.;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Uncertain

0.67

D;D;D;D

MetaSVM

Uncertain

0.40

MutationAssessor

Uncertain

2.3

M;.;M;.

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.6

D;D;D;.

REVEL

Pathogenic

0.74

Sift

Benign

0.055

T;D;D;.

Sift4G

Benign

0.11

T;T;T;T

Polyphen

0.10

B;P;B;.

Vest4

0.92

MutPred

0.57

Gain of sheet (P = 0.1208);.;Gain of sheet (P = 0.1208);.;

MVP

0.38

ClinPred

0.75

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.87

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