rs41310197

chr20-63678287-G-A

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.978G>A(p.Glu326=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0355 in 1,612,566 control chromosomes in the GnomAD database, including 1,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (88 hom., cov: 31)
  • Exomes 𝑓: 0.036 (1056 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.60

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=-0.65).
• BP6: Variant 20-63678287-G-A is Benign according to our data. Variant chr20-63678287-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 473900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63678287-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0282 (4296/152214) while in subpopulation NFE AF= 0.0406 (2762/67994). AF 95% confidence interval is 0.0394. There are 88 homozygotes in gnomad4. There are 2123 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 87 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2	c.978G>A	p.Glu326=	synonymous_variant	12/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1	n.1805G>A		non_coding_transcript_exon_variant	12/38
LOC124904954	XR_007067717.1	n.89C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.978G>A	p.Glu326=	synonymous_variant	12/35	5	NM_001283009.2	A2

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4295 AN: 152096 Hom.: 87 Cov.: 31

Gnomad AFR AF: 0.00729

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00974

Gnomad FIN AF: 0.0539

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0406

Gnomad OTH AF: 0.0354

GnomAD3 exomes AF: 0.0280 AC: 6986 AN: 249554 Hom.: 139 AF XY: 0.0281 AC XY: 3797 AN XY: 135068

Gnomad AFR exome AF: 0.00616

Gnomad AMR exome AF: 0.0213

Gnomad ASJ exome AF: 0.00552

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0107

Gnomad FIN exome AF: 0.0474

Gnomad NFE exome AF: 0.0407

Gnomad OTH exome AF: 0.0296

GnomAD4 exome AF: 0.0362 AC: 52927 AN: 1460352 Hom.: 1056 Cov.: 36 AF XY: 0.0354 AC XY: 25674 AN XY: 726248

Gnomad4 AFR exome AF: 0.00613

Gnomad4 AMR exome AF: 0.0230

Gnomad4 ASJ exome AF: 0.00644

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0117

Gnomad4 FIN exome AF: 0.0479

Gnomad4 NFE exome AF: 0.0414

Gnomad4 OTH exome AF: 0.0325

GnomAD4 genome AF: 0.0282 AC: 4296 AN: 152214 Hom.: 88 Cov.: 31 AF XY: 0.0285 AC XY: 2123 AN XY: 74418

Gnomad4 AFR AF: 0.00727

Gnomad4 AMR AF: 0.0325

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00995

Gnomad4 FIN AF: 0.0539

Gnomad4 NFE AF: 0.0406

Gnomad4 OTH AF: 0.0350

Alfa AF: 0.0317 Hom.: 50

Bravo AF: 0.0252

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0369

EpiControl AF: 0.0372

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 19, 2021

- -

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

- -

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	-0.65
Cadd	Benign	7.4
Dann	Benign	0.67
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs41310197; hg19: chr20-62309640; COSMIC: COSV58898822; COSMIC: COSV58898822;