rs558133631

Positions:

• chr20-63690337-GAGA-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_001283009.2(RTEL1):​c.2313_2315del​(p.Glu771del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,610,860 control chromosomes in the GnomAD database, including 30 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (27 hom.)
• Consequence: RTEL1 NM_001283009.2 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.71

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 -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001283009.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 20-63690337-GAGA-G is Benign according to our data. Variant chr20-63690337-GAGA-G is described in ClinVar as [Likely_benign]. Clinvar id is 436568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00483 (736/152298) while in subpopulation NFE AF= 0.00609 (414/68002). AF 95% confidence interval is 0.0056. There are 3 homozygotes in gnomad4. There are 378 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2	c.2313_2315del	p.Glu771del	inframe_deletion	26/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1	n.3140_3142del		non_coding_transcript_exon_variant	26/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.2313_2315del	p.Glu771del	inframe_deletion	26/35	5	NM_001283009.2	A2

Frequencies

GnomAD3 genomes AF: 0.00484 AC: 737 AN: 152180 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00609

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00555 AC: 1379 AN: 248682 Hom.: 8 AF XY: 0.00538 AC XY: 726 AN XY: 135034

Gnomad AFR exome AF: 0.000748

Gnomad AMR exome AF: 0.00407

Gnomad ASJ exome AF: 0.00182

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00141

Gnomad FIN exome AF: 0.0160

Gnomad NFE exome AF: 0.00708

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.00528 AC: 7695 AN: 1458562 Hom.: 27 AF XY: 0.00510 AC XY: 3701 AN XY: 725464

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.00399

Gnomad4 ASJ exome AF: 0.00257

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00124

Gnomad4 FIN exome AF: 0.0166

Gnomad4 NFE exome AF: 0.00552

Gnomad4 OTH exome AF: 0.00538

GnomAD4 genome AF: 0.00483 AC: 736 AN: 152298 Hom.: 3 Cov.: 33 AF XY: 0.00508 AC XY: 378 AN XY: 74468

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00582

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0158

Gnomad4 NFE AF: 0.00609

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00585 Hom.: 1

Bravo AF: 0.00381

EpiCase AF: 0.00567

EpiControl AF: 0.00605

ClinVar

Significance: Benign/Likely 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	Jul 05, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	RTEL1: PM4:Supporting, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 28, 2015

- -

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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs558133631; hg19: chr20-62321690;