20-63659310-C-T

Variant names:

• chr20-63659310-C-T
• rs2297432
• NM_001283009.2:c.-93C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001283009.2(RTEL1):​c.-93C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 835,946 control chromosomes in the GnomAD database, including 128,547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24680 hom., cov: 33)
  • Exomes 𝑓: 0.54 (103867 hom.)
• Consequence: RTEL1 NM_001283009.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.156

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 20-63659310-C-T is Benign according to our data. Variant chr20-63659310-C-T is described in ClinVar as [Benign]. Clinvar id is 1260129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63659310-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.-93C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 35	ENST00000360203.11	NP_001269938.1
RTEL1	NM_001283009.2	c.-93C>T		5_prime_UTR_variant	Exon 2 of 35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203	c.-93C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582	c.-93C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 35	2		ENSP00000424307.2
RTEL1	ENST00000370018	c.-93C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 35	1		ENSP00000359035.3
RTEL1	ENST00000360203	c.-93C>T		5_prime_UTR_variant	Exon 2 of 35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582	c.-93C>T		5_prime_UTR_variant	Exon 2 of 35	2		ENSP00000424307.2
RTEL1	ENST00000370018	c.-93C>T		5_prime_UTR_variant	Exon 2 of 35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6	n.-93C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 35	5		ENSP00000457428.1
RTEL1-TNFRSF6B	ENST00000492259.6	n.-93C>T		non_coding_transcript_exon_variant	Exon 1 of 35	5		ENSP00000457428.1
RTEL1-TNFRSF6B	ENST00000492259.6	n.-93C>T		5_prime_UTR_variant	Exon 1 of 35	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85327 AN: 151972 Hom.: 24663 Cov.: 33

Gnomad AFR AF: 0.589

Gnomad AMI AF: 0.645

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.580

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.674

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.549

GnomAD4 exome AF: 0.537 AC: 367385 AN: 683856 Hom.: 103867 Cov.: 9 AF XY: 0.533 AC XY: 193787 AN XY: 363618

Gnomad4 AFR exome AF: 0.581

Gnomad4 AMR exome AF: 0.439

Gnomad4 ASJ exome AF: 0.583

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.394

Gnomad4 FIN exome AF: 0.662

Gnomad4 NFE exome AF: 0.583

Gnomad4 OTH exome AF: 0.541

GnomAD4 genome AF: 0.561 AC: 85385 AN: 152090 Hom.: 24680 Cov.: 33 AF XY: 0.561 AC XY: 41685 AN XY: 74352

Gnomad4 AFR AF: 0.589

Gnomad4 AMR AF: 0.517

Gnomad4 ASJ AF: 0.580

Gnomad4 EAS AF: 0.135

Gnomad4 SAS AF: 0.370

Gnomad4 FIN AF: 0.674

Gnomad4 NFE AF: 0.582

Gnomad4 OTH AF: 0.544

Alfa AF: 0.553 Hom.: 6709

Bravo AF: 0.550

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 68% of patients studied by a panel of primary immunodeficiencies. Number of patients: 65. Only high quality variants are reported. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.1
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs2297432; hg19: chr20-62290663; COSMIC: COSV58890541; COSMIC: COSV58890541;