20-63693160-C-T

Variant names:

• chr20-63693160-C-T
• rs398123018
• NM_001283009.2:c.2869C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3 PP3_Moderate PP5

The NM_001283009.2(RTEL1):​c.2869C>T​(p.Arg957Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000428 in 1,612,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000699749: Multiple reports provide experimental evidence that this variant is associated with reduced DNA replication fork function/partner protein interaction in vitro and decreased telomere length in vivo (example, Walne_2013, Takedachi_2020, Touzot_2016). The following publications have been ascertained in the context of this evaluation (PMID:23829372, 23453664, 24582487, 30523160, 32583532, 39279213, 32398829, 29296694)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R957P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:3
• Conservation: PhyloP100: 5.34
• Publications: 15 publications found

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

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000699749: Multiple reports provide experimental evidence that this variant is associated with reduced DNA replication fork function/partner protein interaction in vitro and decreased telomere length in vivo (example, Walne_2013, Takedachi_2020, Touzot_2016). The following publications have been ascertained in the context of this evaluation (PMID: 23829372, 23453664, 24582487, 30523160, 32583532, 39279213, 32398829, 29296694).; SCV005324885: Published functional studies demonstrate telomere shortening, increased T-circle formation, and replication fork stalling (PMID: 23453664, 29296694, 32398829); SCV004722098: Functional studies of patient cells showed significant defects in telomere maintenance (Walne et al 2013. PubMed ID: 23453664).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 20-63693160-C-T is Pathogenic according to our data. Variant chr20-63693160-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42021.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001283009.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	NM_001283009.2	MANE Select	c.2869C>T	p.Arg957Trp	missense	Exon 30 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.2941C>T	p.Arg981Trp	missense	Exon 30 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.2869C>T	p.Arg957Trp	missense	Exon 30 of 35	NP_057518.1	Q9NZ71-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.2869C>T	p.Arg957Trp	missense	Exon 30 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.2941C>T	p.Arg981Trp	missense	Exon 30 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.2869C>T	p.Arg957Trp	missense	Exon 30 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152082 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000401 AC: 10 AN: 249160 AF XY: 0.0000517

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000536

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1459956 Hom.: 0 Cov.: 33 AF XY: 0.0000358 AC XY: 26 AN XY: 726274

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26100

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52070

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1111574

Other (OTH) AF: 0.0000829 AC: 5 AN: 60330

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152082 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74282

African (AFR) AF: 0.00 AC: 0 AN: 41378

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4836

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000281 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000497 AC: 6

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	-	-	Dyskeratosis congenita, autosomal recessive 5 (3)
2	-	-	Dyskeratosis congenita (2)
1	1	-	not provided (2)
1	1	-	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (2)
-	1	-	Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (1)
1	-	-	RTEL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.57		Loss of disorder (P = 0.0476)
MVP		0.73
ClinPred		0.96	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.74
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs398123018; hg19: chr20-62324513; COSMIC: COSV58890761; COSMIC: COSV58890761;