rs6011020

Positions:

• chr20-63673960-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001283009.2(RTEL1):​c.786G>A​(p.Ser262Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00903 in 1,612,716 control chromosomes in the GnomAD database, including 1,124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (584 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (540 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.94

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]

RTEL1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 20-63673960-G-A is Benign according to our data. Variant chr20-63673960-G-A is described in ClinVar as [Benign]. Clinvar id is 473924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.94 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.786G>A	p.Ser262Ser	synonymous_variant	10/35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11	c.786G>A	p.Ser262Ser	synonymous_variant	10/35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7	c.858G>A	p.Ser286Ser	synonymous_variant	10/35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7	c.786G>A	p.Ser262Ser	synonymous_variant	10/35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6	n.786G>A		non_coding_transcript_exon_variant	9/35	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes AF: 0.0476 AC: 7245 AN: 152054 Hom.: 579 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.0278

GnomAD3 exomes AF: 0.0124 AC: 3113 AN: 250610 Hom.: 240 AF XY: 0.00901 AC XY: 1221 AN XY: 135454

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.00728

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000653

Gnomad OTH exome AF: 0.00507

GnomAD4 exome AF: 0.00499 AC: 7290 AN: 1460544 Hom.: 540 Cov.: 32 AF XY: 0.00423 AC XY: 3070 AN XY: 726462

Gnomad4 AFR exome AF: 0.172

Gnomad4 AMR exome AF: 0.00814

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000418

Gnomad4 OTH exome AF: 0.0107

GnomAD4 genome AF: 0.0478 AC: 7276 AN: 152172 Hom.: 584 Cov.: 32 AF XY: 0.0466 AC XY: 3464 AN XY: 74386

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.0160

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.0275

Alfa AF: 0.0261 Hom.: 170

Bravo AF: 0.0538

Asia WGS AF: 0.00982 AC: 35 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Dyskeratosis congenita Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.34
DANN	Benign	0.70
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs6011020; hg19: chr20-62305313;