rs61736615

chr20-63692937-G-Achr20-63692937-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001283009.2(RTEL1):c.2785G>A(p.Ala929Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0333 in 1,612,586 control chromosomes in the GnomAD database, including 1,007 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict 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. A929A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.026 (57 hom., cov: 33)
  • Exomes 𝑓: 0.034 (950 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.375

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002790749).
• BP6: Variant 20-63692937-G-A is Benign according to our data. Variant chr20-63692937-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 473914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63692937-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.026 (3956/152306) while in subpopulation NFE AF= 0.0376 (2558/68004). AF 95% confidence interval is 0.0364. There are 57 homozygotes in gnomad4. There are 1883 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 57 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2	c.2785G>A	p.Ala929Thr	missense_variant	29/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1	n.3612G>A		non_coding_transcript_exon_variant	29/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.2785G>A	p.Ala929Thr	missense_variant	29/35	5	NM_001283009.2	A2

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 3956 AN: 152188 Hom.: 57 Cov.: 33

Gnomad AFR AF: 0.00828

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00951

Gnomad FIN AF: 0.0360

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0376

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0274 AC: 6839 AN: 249762 Hom.: 118 AF XY: 0.0284 AC XY: 3846 AN XY: 135584

Gnomad AFR exome AF: 0.00696

Gnomad AMR exome AF: 0.0189

Gnomad ASJ exome AF: 0.0249

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0128

Gnomad FIN exome AF: 0.0378

Gnomad NFE exome AF: 0.0394

Gnomad OTH exome AF: 0.0302

GnomAD4 exome AF: 0.0341 AC: 49732 AN: 1460280 Hom.: 950 Cov.: 33 AF XY: 0.0339 AC XY: 24660 AN XY: 726438

Gnomad4 AFR exome AF: 0.00606

Gnomad4 AMR exome AF: 0.0201

Gnomad4 ASJ exome AF: 0.0255

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0130

Gnomad4 FIN exome AF: 0.0378

Gnomad4 NFE exome AF: 0.0386

Gnomad4 OTH exome AF: 0.0315

GnomAD4 genome AF: 0.0260 AC: 3956 AN: 152306 Hom.: 57 Cov.: 33 AF XY: 0.0253 AC XY: 1883 AN XY: 74466

Gnomad4 AFR AF: 0.00828

Gnomad4 AMR AF: 0.0286

Gnomad4 ASJ AF: 0.0265

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00952

Gnomad4 FIN AF: 0.0360

Gnomad4 NFE AF: 0.0376

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0318 Hom.: 41

Bravo AF: 0.0252

TwinsUK AF: 0.0396 AC: 147

ALSPAC AF: 0.0418 AC: 161

ESP6500AA AF: 0.0107 AC: 47

ESP6500EA AF: 0.0370 AC: 318

ExAC AF: 0.0271 AC: 3273

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.0375

EpiControl AF: 0.0419

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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

Jun 03, 2022

See Variant Classification Assertion Criteria. -

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

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	3.1
Dann	Benign	0.89
DEOGEN2	Benign	0.10	T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.54	T;T;T;T
MetaRNN	Benign	0.0028	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.30	N;N;N;.
REVEL	Benign	0.023
Sift	Benign	0.095	T;T;T;.
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.21	B;P;P;.
Vest4		0.076
ClinPred		0.0023	T
GERP RS		-5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.16

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

Publications

LitVar

Other links and lift over

dbSNP: rs61736615; hg19: chr20-62324290; COSMIC: COSV58898629; COSMIC: COSV58898629;