rs146221660

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001283009.2(RTEL1):c.2957G>A(p.Arg986Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,611,840 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 1 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:6

Conservation

PhyloP100: -0.682

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:

RTEL1 (HGNC:):

RTEL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.032576203).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTEL1	NM_001283009.2 linkuse as main transcript	c.2957G>A	p.Arg986Gln	missense_variant	30/35	ENST00000360203.11	NP_001269938.1	Q9NZ71-6R4IXY3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RTEL1	ENST00000360203.11 linkuse as main transcript	c.2957G>A	p.Arg986Gln	missense_variant	30/35	5	NM_001283009.2	ENSP00000353332.5	Q9NZ71-6
RTEL1	ENST00000508582.7 linkuse as main transcript	c.3029G>A	p.Arg1010Gln	missense_variant	30/35	2		ENSP00000424307.2	Q9NZ71-7
RTEL1	ENST00000370018.7 linkuse as main transcript	c.2957G>A	p.Arg986Gln	missense_variant	30/35	1		ENSP00000359035.3	Q9NZ71-1
RTEL1-TNFRSF6B	ENST00000492259.6 linkuse as main transcript	n.*559G>A		non_coding_transcript_exon_variant	27/35	5		ENSP00000457428.1	D6RA96
RTEL1-TNFRSF6B	ENST00000492259.6 linkuse as main transcript	n.*559G>A		3_prime_UTR_variant	27/35	5		ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000282

AC:

AN:

248534

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135002

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000269

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000432

AC:

AN:

1459814

Hom.:

Cov.:

AF XY:

0.0000386

AC XY:

AN XY:

726212

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152026

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.0000967

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000249

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 15, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pulmonary fibrosis and/or bone marrow failure, telomere-related, 3 (MIM#616373). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 9 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been previously reported as pathogenic in a family (2 tested individuals) with familial interstitial pneumonia (PMID: 25607374) and also as a VUS (ClinVar, global variome LOVD). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Interstitial lung disease 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

University of Washington Center for Mendelian Genomics, University of Washington

May 19, 2015

- -

Dyskeratosis congenita, autosomal recessive 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 23, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 04, 2023

Identified in an individual with familial interstitial pneumonia in published literature (Cogan et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.2957G>A; p.(R986Q); This variant is associated with the following publications: (PMID: 25607374) -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 986 of the RTEL1 protein (p.Arg986Gln). This variant is present in population databases (rs146221660, gnomAD 0.01%). This missense change has been observed in individual(s) with familial interstitial pneumonia (PMID: 25607374). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

RTEL1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 02, 2023

The RTEL1 c.3029G>A variant is predicted to result in the amino acid substitution p.Arg1010Gln. This variant was reported in an individual with familial interstitial pneumonia (Cogan et al. 2015. PubMed ID: 25607374). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-62324601-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Dyskeratosis congenita

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 18, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.077

DANN

Benign

0.91

DEOGEN2

Benign

0.090

T;.;.;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.59

T;T;T;T

M_CAP

Benign

0.0053

MetaRNN

Benign

0.033

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

N;.;N;.

PrimateAI

Benign

0.18

PROVEAN

Benign

-0.77

N;N;N;.

REVEL

Benign

0.0090

Sift

Benign

0.70

T;T;T;.

Sift4G

Benign

0.81

T;T;T;T

Polyphen

0.022

B;B;B;.

Vest4

0.15

MVP

0.42

ClinPred

0.016

GERP RS

-9.6

Varity_R

0.023

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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