rs963605629

Variant names:

• chr20-63666045-A-G
• rs963605629
• NM_001283009.2:c.580A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001283009.2(RTEL1):​c.580A>G​(p.Ile194Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000185 in 1,461,834 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 (★★). Synonymous variant affecting the same amino acid position (i.e. I194I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.83
• Publications: 0 publications found

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-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]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27224904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.580A>G	p.Ile194Val	missense_variant	Exon 7 of 35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11	c.580A>G	p.Ile194Val	missense_variant	Exon 7 of 35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7	c.652A>G	p.Ile218Val	missense_variant	Exon 7 of 35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7	c.580A>G	p.Ile194Val	missense_variant	Exon 7 of 35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6	n.580A>G		non_coding_transcript_exon_variant	Exon 6 of 35	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461834 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I194V variant (also known as c.580A>G), located in coding exon 6 of the RTEL1 gene, results from an A to G substitution at nucleotide position 580. The isoleucine at codon 194 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Uncertain:1

Dec 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 194 of the RTEL1 protein (p.Ile194Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RTEL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 473923). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Dyskeratosis congenita Uncertain:1

Aug 03, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.7	L;.;L;.
PhyloP100		5.8
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.65	N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.15	T;T;T;D
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.86	P;B;P;.
Vest4		0.24
MutPred		0.56		Gain of ubiquitination at K199 (P = 0.0817);.;Gain of ubiquitination at K199 (P = 0.0817);.;
MVP		0.15
ClinPred		0.81	D
GERP RS		5.2
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.11
gMVP		0.36
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs963605629; hg19: chr20-62297398;