20-63692830-C-T

Variant names:

• chr20-63692830-C-T
• rs141717966
• NM_001283009.2:c.2678C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001283009.2(RTEL1):​c.2678C>T​(p.Thr893Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,612,304 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T893R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -1.94
• Publications: 6 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006728679).
• BP6: Variant 20-63692830-C-T is Benign according to our data. Variant chr20-63692830-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540965.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001283009.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	NM_001283009.2	MANE Select	c.2678C>T	p.Thr893Met	missense	Exon 29 of 35	NP_001269938.1
	RTEL1	NM_032957.5		c.2750C>T	p.Thr917Met	missense	Exon 29 of 35	NP_116575.3
	RTEL1	NM_016434.4		c.2678C>T	p.Thr893Met	missense	Exon 29 of 35	NP_057518.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.2678C>T	p.Thr893Met	missense	Exon 29 of 35	ENSP00000353332.5
	RTEL1	ENST00000508582.7	TSL:2	c.2750C>T	p.Thr917Met	missense	Exon 29 of 35	ENSP00000424307.2
	RTEL1	ENST00000370018.7	TSL:1	c.2678C>T	p.Thr893Met	missense	Exon 29 of 35	ENSP00000359035.3

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000417 AC: 104 AN: 249244 AF XY: 0.000443

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00301

Gnomad EAS exome AF: 0.00147

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000196

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000272 AC: 397 AN: 1459954 Hom.: 0 Cov.: 30 AF XY: 0.000277 AC XY: 201 AN XY: 726222

African (AFR) AF: 0.000209 AC: 7 AN: 33472

American (AMR) AF: 0.000358 AC: 16 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00356 AC: 93 AN: 26122

East Asian (EAS) AF: 0.000932 AC: 37 AN: 39692

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86248

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52058

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5696

European-Non Finnish (NFE) AF: 0.000163 AC: 181 AN: 1111634

Other (OTH) AF: 0.000514 AC: 31 AN: 60340

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74494

African (AFR) AF: 0.000216 AC: 9 AN: 41572

American (AMR) AF: 0.000457 AC: 7 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68026

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000484 Hom.: 0

Bravo AF: 0.000355

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000349 AC: 42

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Sep 12, 2022

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the RTEL1 gene demonstrated a sequence change, c.2750C>T, in exon 29 that results in an amino acid change, p.Thr917Met. This sequence change does not appear to have been previously described in patients with RTEL1-related disorders and has been described in the gnomAD database with a frequency of 0.3% in the Ashkenazi Jewish sub-population (dbSNP rs141717966). The p.Thr917Met change affects a poorly conserved amino acid residue located in a domain of the RTEL1 protein that is not known to be functional. The p.Thr917Met substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Thr917Met change remains unknown at this time.

not provided Uncertain:1

Jan 31, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in any cases, but was observed in unaffected controls from a melanoma study (PMID: 29641532); This variant is associated with the following publications: (PMID: 29641532)

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dyskeratosis congenita Benign:1

Feb 07, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.045
DANN	Benign	0.91
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.12	N
PhyloP100		-1.9
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.0070
Sift	Benign	0.14	T
Sift4G	Benign	0.10	T
Polyphen		0.0020	B
Vest4		0.10
MVP		0.32
ClinPred		0.014	T
GERP RS		-9.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.32
Mutation Taster		=95/5	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: rs141717966; hg19: chr20-62324183;