rs963605629

Positions:

• chr20-63666045-A-G

Variant summary

Our verdict is Likely benign. Variant got -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, single submitter U:2
• Conservation: PhyloP100: 5.83

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:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.580A>G	p.Ile194Val	missense_variant	7/35	ENST00000360203.11	NP_001269938.1
RTEL1-TNFRSF6B	NR_037882.1	n.1407A>G		non_coding_transcript_exon_variant	7/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11	c.580A>G	p.Ile194Val	missense_variant	7/35	5	NM_001283009.2	ENSP00000353332	A2

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

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: 0.0000243

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Dec 02, 2021

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

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 03, 2021

- -

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;.
MutationTaster	Benign	1.0	D;D;D;D
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

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

Other links and lift over

dbSNP: rs963605629; hg19: chr20-62297398;