chr20-63690935-T-C

Variant names:

• chr20-63690935-T-C
• rs3208007
• NM_001283009.2:c.2544T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001283009.2(RTEL1):​c.2544T>C​(p.Pro848Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.761 in 1,553,268 control chromosomes in the GnomAD database, including 456,312 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P848P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.80 (50420 hom., cov: 34)
  • Exomes 𝑓: 0.76 (405892 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -2.58
• Publications: 37 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 20-63690935-T-C is Benign according to our data. Variant chr20-63690935-T-C is described in ClinVar as Benign. ClinVar VariationId is 403401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.931 is higher than 0.05.

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.2544T>C	p.Pro848Pro	synonymous	Exon 27 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.2616T>C	p.Pro872Pro	synonymous	Exon 27 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.2544T>C	p.Pro848Pro	synonymous	Exon 27 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.2544T>C	p.Pro848Pro	synonymous	Exon 27 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.2616T>C	p.Pro872Pro	synonymous	Exon 27 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.2544T>C	p.Pro848Pro	synonymous	Exon 27 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.804 AC: 122271 AN: 152006 Hom.: 50359 Cov.: 34

Gnomad AFR AF: 0.938

Gnomad AMI AF: 0.814

Gnomad AMR AF: 0.772

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.725

Gnomad FIN AF: 0.800

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.777

Gnomad OTH AF: 0.795

GnomAD2 exomes AF: 0.739 AC: 118199 AN: 159858 AF XY: 0.737

Gnomad AFR exome AF: 0.943

Gnomad AMR exome AF: 0.741

Gnomad ASJ exome AF: 0.769

Gnomad EAS exome AF: 0.286

Gnomad FIN exome AF: 0.806

Gnomad NFE exome AF: 0.779

Gnomad OTH exome AF: 0.756

GnomAD4 exome AF: 0.756 AC: 1059519 AN: 1401142 Hom.: 405892 Cov.: 61 AF XY: 0.756 AC XY: 522571 AN XY: 691670

African (AFR) AF: 0.950 AC: 30383 AN: 31978

American (AMR) AF: 0.739 AC: 26662 AN: 36070

Ashkenazi Jewish (ASJ) AF: 0.771 AC: 19397 AN: 25146

East Asian (EAS) AF: 0.307 AC: 11213 AN: 36574

South Asian (SAS) AF: 0.733 AC: 58533 AN: 79854

European-Finnish (FIN) AF: 0.804 AC: 38617 AN: 48020

Middle Eastern (MID) AF: 0.780 AC: 3361 AN: 4310

European-Non Finnish (NFE) AF: 0.766 AC: 827900 AN: 1081202

Other (OTH) AF: 0.749 AC: 43453 AN: 57988

GnomAD4 genome AF: 0.805 AC: 122393 AN: 152126 Hom.: 50420 Cov.: 34 AF XY: 0.800 AC XY: 59538 AN XY: 74376

African (AFR) AF: 0.938 AC: 38965 AN: 41526

American (AMR) AF: 0.772 AC: 11799 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 2666 AN: 3470

East Asian (EAS) AF: 0.292 AC: 1496 AN: 5130

South Asian (SAS) AF: 0.725 AC: 3502 AN: 4830

European-Finnish (FIN) AF: 0.800 AC: 8489 AN: 10616

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.777 AC: 52824 AN: 67942

Other (OTH) AF: 0.792 AC: 1675 AN: 2114

Alfa AF: 0.787 Hom.: 26937

Bravo AF: 0.805

Asia WGS AF: 0.551 AC: 1920 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	-	4	not specified (4)
-	-	1	Dyskeratosis congenita (1)
-	-	1	Dyskeratosis congenita, autosomal recessive 5 (1)
-	-	1	Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (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_noAF	Benign	-0.91
CADD	Benign	0.069
DANN	Benign	0.60
PhyloP100		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs3208007; hg19: chr20-62322288; COSMIC: COSV58890552; COSMIC: COSV58890552;