20-63693211-C-T

Variant names:

• chr20-63693211-C-T
• rs398123017
• NM_001283009.2:c.2920C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_001283009.2(RTEL1):​c.2920C>T​(p.Arg974*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000571 in 1,611,994 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005400720: The functional study showed that Arg974Ter transcript was degraded by nonsense-mediated decay and cells with variant showed significantly shortening telomeres (Walne et al., 2013" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R974R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: RTEL1 NM_001283009.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 0.632
• Publications: 17 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: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005400720: The functional study showed that Arg974Ter transcript was degraded by nonsense-mediated decay and cells with variant showed significantly shortening telomeres (Walne et al., 2013; Deng et al., 2013).; SCV000699750: The functional study showed that R974X transcript was degraded by nonsense-mediated decay (Deng_2013), and cells with variant showed significantly shortening telomeres (Deng_2013, Walne_2013) compare to WT.; SCV001365924: "In vitro functional studies provide evidence that the p.Arg998X variant impacts protein function (Deng 2013)."; SCV001780628: Published functional studies demonstrate a damaging effect on telomere function, structure, and length (PMID: 23959892); SCV002547359: leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted; SCV004239045: This nonsense variant results in a premature stop codon in exon 30 of 35, likely leading to nonsense-mediated decay and lack of protein production, which is supported by a functional study.
• PP5: Variant 20-63693211-C-T is Pathogenic according to our data. Variant chr20-63693211-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 42020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2920C>T	p.Arg974*	stop_gained	Exon 30 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.2992C>T	p.Arg998*	stop_gained	Exon 30 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.2920C>T	p.Arg974*	stop_gained	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.2920C>T	p.Arg974*	stop_gained	Exon 30 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.2992C>T	p.Arg998*	stop_gained	Exon 30 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.2920C>T	p.Arg974*	stop_gained	Exon 30 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152040 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000321 AC: 8 AN: 249302 AF XY: 0.0000369

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000625

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000555 AC: 81 AN: 1459954 Hom.: 0 Cov.: 33 AF XY: 0.0000661 AC XY: 48 AN XY: 726288

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000612 AC: 68 AN: 1111560

Other (OTH) AF: 0.0000663 AC: 4 AN: 60334

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152040 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74244

African (AFR) AF: 0.000121 AC: 5 AN: 41362

American (AMR) AF: 0.000131 AC: 2 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67970

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000475 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.41	N
PhyloP100		0.63
Vest4		0.77
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs398123017; hg19: chr20-62324564;