rs41302954

chr20-63678161-G-Achr20-63678161-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001283009.2(RTEL1):c.936G>A(p.Leu312=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,614,118 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L312L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0095 (11 hom., cov: 29)
  • Exomes 𝑓: 0.012 (122 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0230

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:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 20-63678161-G-A is Benign according to our data. Variant chr20-63678161-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 473897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63678161-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.023 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00947 (1442/152316) while in subpopulation NFE AF= 0.0144 (982/68024). AF 95% confidence interval is 0.0137. There are 11 homozygotes in gnomad4. There are 710 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2	c.936G>A	p.Leu312=	synonymous_variant	11/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1	n.1763G>A		non_coding_transcript_exon_variant	11/38
LOC124904954	XR_007067717.1	n.215C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.936G>A	p.Leu312=	synonymous_variant	11/35	5	NM_001283009.2	A2

Frequencies

GnomAD3 genomes AF: 0.00947 AC: 1442 AN: 152198 Hom.: 11 Cov.: 29

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0101 AC: 2527 AN: 251278 Hom.: 24 AF XY: 0.0102 AC XY: 1387 AN XY: 135850

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.0280

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00850

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.0117 AC: 17066 AN: 1461802 Hom.: 122 Cov.: 31 AF XY: 0.0116 AC XY: 8469 AN XY: 727196

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.00499

Gnomad4 ASJ exome AF: 0.0272

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00894

Gnomad4 FIN exome AF: 0.0125

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.00947 AC: 1442 AN: 152316 Hom.: 11 Cov.: 29 AF XY: 0.00953 AC XY: 710 AN XY: 74476

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.0130

Gnomad4 NFE AF: 0.0144

Gnomad4 OTH AF: 0.0157

Alfa AF: 0.0130 Hom.: 7

Bravo AF: 0.00825

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0135

EpiControl AF: 0.0130

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	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RTEL1: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2020	- -

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

Feb 01, 2024

- -

Dyskeratosis congenita Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	7.7
Dann	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs41302954; hg19: chr20-62309514;