20-63693266-C-T

Variant names:

• chr20-63693266-C-T
• rs143967591
• NM_001283009.2:c.2975C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001283009.2(RTEL1):​c.2975C>T​(p.Pro992Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,611,800 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P992R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (6 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.461
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00494954).
• BP6: Variant 20-63693266-C-T is Benign according to our data. Variant chr20-63693266-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0011 (1606/1459670) while in subpopulation MID AF = 0.00956 (55/5756). AF 95% confidence interval is 0.00754. There are 6 homozygotes in GnomAdExome4. There are 903 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,AD gene

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.2975C>T	p.Pro992Leu	missense	Exon 30 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.3047C>T	p.Pro1016Leu	missense	Exon 30 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.2975C>T	p.Pro992Leu	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.2975C>T	p.Pro992Leu	missense	Exon 30 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.3047C>T	p.Pro1016Leu	missense	Exon 30 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.2975C>T	p.Pro992Leu	missense	Exon 30 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.000928 AC: 141 AN: 152012 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00145 AC: 360 AN: 247790 AF XY: 0.00170

Gnomad AFR exome AF: 0.000810

Gnomad AMR exome AF: 0.000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000604

Gnomad NFE exome AF: 0.000803

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.00110 AC: 1606 AN: 1459670 Hom.: 6 Cov.: 33 AF XY: 0.00124 AC XY: 903 AN XY: 726138

African (AFR) AF: 0.000568 AC: 19 AN: 33472

American (AMR) AF: 0.00116 AC: 52 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26086

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39700

South Asian (SAS) AF: 0.00579 AC: 499 AN: 86256

European-Finnish (FIN) AF: 0.000616 AC: 32 AN: 51970

Middle Eastern (MID) AF: 0.00956 AC: 55 AN: 5756

European-Non Finnish (NFE) AF: 0.000755 AC: 839 AN: 1111448

Other (OTH) AF: 0.00164 AC: 99 AN: 60316

GnomAD4 genome AF: 0.000927 AC: 141 AN: 152130 Hom.: 0 Cov.: 33 AF XY: 0.000888 AC XY: 66 AN XY: 74364

African (AFR) AF: 0.00113 AC: 47 AN: 41456

American (AMR) AF: 0.000982 AC: 15 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00393 AC: 19 AN: 4834

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10628

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 67956

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000716 Hom.: 0

Bravo AF: 0.000929

ESP6500AA AF: 0.000684 AC: 3

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.00154 AC: 185

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	4.4
DANN	Benign	0.81
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-0.46
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.17
Sift	Benign	0.47	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.36
ClinPred		0.0011	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.25
Mutation Taster		=97/3	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: rs143967591; hg19: chr20-62324619; COSMIC: COSV58900179; COSMIC: COSV58900179;