NM_001283009.2:c.2652+4C>T

Variant names:

• chr20-63691841-C-T
• rs374540895
• NM_001283009.2:c.2652+4C>T

Variant summary

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

The NM_001283009.2(RTEL1):​c.2652+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,607,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: RTEL1 NM_001283009.2 splice_region, intron
• Scores: Splicing: ADA: 0.001050
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -2.49
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.2652+4C>T		splice_region_variant, intron_variant	Intron 28 of 34	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11	c.2652+4C>T		splice_region_variant, intron_variant	Intron 28 of 34	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7	c.2724+4C>T		splice_region_variant, intron_variant	Intron 28 of 34	2		ENSP00000424307.2
RTEL1	ENST00000370018.7	c.2652+4C>T		splice_region_variant, intron_variant	Intron 28 of 34	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6	n.*254+4C>T		splice_region_variant, intron_variant	Intron 25 of 34	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152074 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000147 AC: 36 AN: 244174 AF XY: 0.000143

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000803

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000537

Gnomad NFE exome AF: 0.0000727

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000103 AC: 150 AN: 1455274 Hom.: 0 Cov.: 30 AF XY: 0.000112 AC XY: 81 AN XY: 724202

African (AFR) AF: 0.00117 AC: 39 AN: 33442

American (AMR) AF: 0.0000671 AC: 3 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86218

European-Finnish (FIN) AF: 0.0000205 AC: 1 AN: 48692

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5744

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1110396

Other (OTH) AF: 0.000299 AC: 18 AN: 60282

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.000417 AC XY: 31 AN XY: 74406

African (AFR) AF: 0.000843 AC: 35 AN: 41542

American (AMR) AF: 0.000196 AC: 3 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000315 Hom.: 0

Bravo AF: 0.000412

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dyskeratosis congenita, autosomal dominant 1 Uncertain:1

Jun 05, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 28 of the RTEL1 gene. It does not directly change the encoded amino acid sequence of the RTEL1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs374540895, gnomAD 0.1%). 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: 540941). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.094
DANN	Benign	0.91
PhyloP100		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0010
dbscSNV1_RF	Benign	0.074
SpliceAI score (max)		0.12		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: rs374540895; hg19: chr20-62323194;