rs115610405

Positions:

• chr20-63694480-C-A

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.3101C>A​(p.Pro1034His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,597,222 control chromosomes in the GnomAD database, including 342 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (43 hom., cov: 31)
  • Exomes 𝑓: 0.018 (299 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.196

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027760863).
• BP6: Variant 20-63694480-C-A is Benign according to our data. Variant chr20-63694480-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 473917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63694480-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0158 (2402/152326) while in subpopulation NFE AF= 0.0201 (1367/68028). AF 95% confidence interval is 0.0192. There are 43 homozygotes in gnomad4. There are 1222 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 43 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.3101C>A	p.Pro1034His	missense_variant	31/35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11	c.3101C>A	p.Pro1034His	missense_variant	31/35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7	c.3173C>A	p.Pro1058His	missense_variant	31/35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7	c.3101C>A	p.Pro1034His	missense_variant	31/35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6	n.*703C>A		non_coding_transcript_exon_variant	28/35	5		ENSP00000457428.1
RTEL1-TNFRSF6B	ENST00000492259.6	n.*703C>A		3_prime_UTR_variant	28/35	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2401 AN: 152208 Hom.: 43 Cov.: 31

Gnomad AFR AF: 0.00415

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.0517

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0161 AC: 3944 AN: 244392 Hom.: 54 AF XY: 0.0163 AC XY: 2166 AN XY: 133126

Gnomad AFR exome AF: 0.00338

Gnomad AMR exome AF: 0.00830

Gnomad ASJ exome AF: 0.00688

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000726

Gnomad FIN exome AF: 0.0474

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0208

GnomAD4 exome AF: 0.0182 AC: 26335 AN: 1444896 Hom.: 299 Cov.: 32 AF XY: 0.0178 AC XY: 12761 AN XY: 715800

Gnomad4 AFR exome AF: 0.00280

Gnomad4 AMR exome AF: 0.00908

Gnomad4 ASJ exome AF: 0.00711

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000793

Gnomad4 FIN exome AF: 0.0461

Gnomad4 NFE exome AF: 0.0202

Gnomad4 OTH exome AF: 0.0167

GnomAD4 genome AF: 0.0158 AC: 2402 AN: 152326 Hom.: 43 Cov.: 31 AF XY: 0.0164 AC XY: 1222 AN XY: 74482

Gnomad4 AFR AF: 0.00414

Gnomad4 AMR AF: 0.0144

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.0517

Gnomad4 NFE AF: 0.0201

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0185 Hom.: 22

Bravo AF: 0.0131

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0197 AC: 76

ESP6500AA AF: 0.00574 AC: 25

ESP6500EA AF: 0.0191 AC: 163

ExAC AF: 0.0159 AC: 1911

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0192

EpiControl AF: 0.0202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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)	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 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

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
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	8.0
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;.;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.58	T;T;T;T
MetaRNN	Benign	0.0028	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.6	L;.;L;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.2	N;N;N;.
REVEL	Benign	0.26
Sift	Benign	0.40	T;T;T;.
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.94	P;D;D;.
Vest4		0.26
ClinPred		0.0065	T
GERP RS		-0.64
Varity_R		0.080
gMVP		0.23

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: rs115610405; hg19: chr20-62325833;