rs398123049

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001283009.2(RTEL1):c.2233G>A(p.Val745Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,244 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 4.54

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32175025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2 link	c.2233G>A	p.Val745Met	missense_variant	Exon 25 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.2233G>A	p.Val745Met	missense_variant	Exon 25 of 35	5	NM_001283009.2	ENSP00000353332.5	Q9NZ71-6
RTEL1	ENST00000508582.7 link	c.2305G>A	p.Val769Met	missense_variant	Exon 25 of 35	2		ENSP00000424307.2	Q9NZ71-7
RTEL1	ENST00000370018.7 link	c.2233G>A	p.Val745Met	missense_variant	Exon 25 of 35	1		ENSP00000359035.3	Q9NZ71-1
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.2226-116G>A		intron_variant	Intron 22 of 34	5		ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460244

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726432

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:2

Mar 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 745 of the RTEL1 protein (p.Val745Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Hoyeraal‚Äö√Ñ√¨ Hreidarsson syndrome (PMID: 23591994). ClinVar contains an entry for this variant (Variation ID: 65414). 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. 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. -

Aug 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dyskeratosis congenita, autosomal recessive 5

Pathogenic:1

Aug 15, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;.;.;.;.

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.86

D;D;D;T;D

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.32

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;.;M;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.1

N;N;N;.;N

REVEL

Benign

0.11

Sift

Benign

0.079

T;T;T;.;T

Sift4G

Benign

0.086

T;T;T;T;T

Polyphen

0.91

P;D;P;.;.

Vest4

0.73

MutPred

0.44

Loss of helix (P = 0.0237);.;Loss of helix (P = 0.0237);.;.;

MVP

0.37

ClinPred

0.92

GERP RS

3.8

Varity_R

0.10

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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