20-63659310-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 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: Benign. The variant received -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.
• 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	ENST00000360203.11	c.-93C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7	c.-93C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7	c.-93C>T		5_prime_UTR_premature_start_codon_gain_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	ENST00000360203.11	c.-93C>T		5_prime_UTR_variant	Exon 2 of 35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7	c.-93C>T		5_prime_UTR_variant	Exon 2 of 35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7	c.-93C>T		5_prime_UTR_variant	Exon 2 of 35	1		ENSP00000359035.3
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

African (AFR) AF: 0.581 AC: 10809 AN: 18600

American (AMR) AF: 0.439 AC: 16380 AN: 37274

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 11969 AN: 20540

East Asian (EAS) AF: 0.123 AC: 4265 AN: 34678

South Asian (SAS) AF: 0.394 AC: 26293 AN: 66650

European-Finnish (FIN) AF: 0.662 AC: 33057 AN: 49916

Middle Eastern (MID) AF: 0.549 AC: 1585 AN: 2886

European-Non Finnish (NFE) AF: 0.583 AC: 244233 AN: 418586

Other (OTH) AF: 0.541 AC: 18794 AN: 34726

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

African (AFR) AF: 0.589 AC: 24429 AN: 41474

American (AMR) AF: 0.517 AC: 7896 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 2013 AN: 3470

East Asian (EAS) AF: 0.135 AC: 700 AN: 5188

South Asian (SAS) AF: 0.370 AC: 1781 AN: 4818

European-Finnish (FIN) AF: 0.674 AC: 7125 AN: 10572

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.582 AC: 39538 AN: 67984

Other (OTH) AF: 0.544 AC: 1147 AN: 2110

Alfa AF: 0.560 Hom.: 19069

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

- -

-

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

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. -

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
PhyloP100		-0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

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