rs143461704

Variant names:

• chr20-63661440-C-T
• rs143461704
• NM_001283009.2:c.245C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001283010.1(RTEL1):​c.-425C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000942 in 1,613,490 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: RTEL1 NM_001283010.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: -0.368
• Publications: 7 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.043679267).
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,SD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001283010.1. 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.245C>T	p.Pro82Leu	missense	Exon 3 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_001283010.1		c.-425C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 34	NP_001269939.1	Q9NZ71-9
	RTEL1	NM_032957.5		c.245C>T	p.Pro82Leu	missense	Exon 3 of 35	NP_116575.3	Q9NZ71-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.245C>T	p.Pro82Leu	missense	Exon 3 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.245C>T	p.Pro82Leu	missense	Exon 3 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.245C>T	p.Pro82Leu	missense	Exon 3 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000299 AC: 75 AN: 250654 AF XY: 0.000258

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000600

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000998 AC: 1459 AN: 1461334 Hom.: 2 Cov.: 32 AF XY: 0.000970 AC XY: 705 AN XY: 726986

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.0000567 AC: 3 AN: 52898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00121 AC: 1345 AN: 1111996

Other (OTH) AF: 0.00169 AC: 102 AN: 60388

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.000323 AC XY: 24 AN XY: 74332

African (AFR) AF: 0.000217 AC: 9 AN: 41422

American (AMR) AF: 0.000131 AC: 2 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68038

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

Alfa AF: 0.000781 Hom.: 1

Bravo AF: 0.000434

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000763

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (3)
-	2	-	not provided (2)
-	1	-	Dyskeratosis congenita, autosomal dominant 1 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	1	-	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	Benign	0.073
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.050
DANN	Benign	0.78
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.37
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.27
Sift	Benign	0.59	T
Sift4G	Benign	0.50	T
Polyphen		0.0020	B
Vest4		0.12
MVP		0.51
ClinPred		0.027	T
GERP RS		-9.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.51
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs143461704; hg19: chr20-62292793; COSMIC: COSV58894811; COSMIC: COSV58894811;