chr20-63695418-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001283009.2(RTEL1):c.3590G>C(p.Gly1197Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,562,816 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1197S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000091 ( 1 hom. )

Consequence

RTEL1
NM_001283009.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: -0.665

Publications

1 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

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005782455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2 link	c.3590G>C	p.Gly1197Ala	missense_variant	Exon 34 of 35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RTEL1	ENST00000360203.11 link	c.3590G>C	p.Gly1197Ala	missense_variant	Exon 34 of 35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7 link	c.3662G>C	p.Gly1221Ala	missense_variant	Exon 34 of 35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7 link	c.3590G>C	p.Gly1197Ala	missense_variant	Exon 34 of 35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.*1192G>C		non_coding_transcript_exon_variant	Exon 31 of 35	5		ENSP00000457428.1
RTEL1-TNFRSF6B	ENST00000492259.6 link	n.*1192G>C		3_prime_UTR_variant	Exon 31 of 35	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

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:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000173

AC:

AN:

207938

AF XY:

0.000117

show subpopulations

Gnomad AFR exome

AF:

0.000128

Gnomad AMR exome

AF:

0.000666

Gnomad ASJ exome

AF:

0.000336

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.000403

GnomAD4 exome

AF:

0.0000907

AC:

128

AN:

1410500

Hom.:

Cov.:

AF XY:

0.0000820

AC XY:

AN XY:

695518

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32388

American (AMR)

AF:

0.000926

AC:

AN:

39954

Ashkenazi Jewish (ASJ)

AF:

0.000535

AC:

AN:

22436

East Asian (EAS)

AF:

0.00

AC:

AN:

39262

South Asian (SAS)

AF:

0.0000129

AC:

AN:

77752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49632

Middle Eastern (MID)

AF:

0.000363

AC:

AN:

5508

European-Non Finnish (NFE)

AF:

0.0000507

AC:

AN:

1085414

Other (OTH)

AF:

0.000361

AC:

AN:

58154

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

Exome Hom

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:

0.000315

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41576

American (AMR)

AF:

0.00255

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.000251

Hom.:

Bravo

AF:

0.000631

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000192

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Feb 09, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in an individual with nonalcoholic fatty liver disease associated hepatocellular carcinoma in published literature (Pelusi 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30842500) -

Nov 26, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dyskeratosis congenita

Uncertain:2

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 03, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

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

Uncertain:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1197 of the RTEL1 protein (p.Gly1197Ala). This variant is present in population databases (rs138500086, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with RTEL1-related conditions. This variant is also known as c.3662G>C (p.Gly1221Ala). ClinVar contains an entry for this variant (Variation ID: 573419). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The alanine 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.90

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.098

T;.;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.51

T;T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.0058

T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-0.34

N;.;N;.

PhyloP100

-0.67

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.32

N;N;N;.

REVEL

Benign

0.067

Sift

Benign

1.0

T;T;T;.

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0030

B;B;B;.

Vest4

0.10

MVP

0.52

ClinPred

0.0088

GERP RS

-0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.036

gMVP

0.23

Mutation Taster

=100/0

polymorphism

(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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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