rs6062302

Variant names:

• chr20-63689615-T-C
• rs6062302
• NM_001283009.2:c.1992T>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.1992T>C​(p.Asp664Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.76 in 1,611,728 control chromosomes in the GnomAD database, including 472,506 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (50335 hom., cov: 32)
  • Exomes 𝑓: 0.76 (422171 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 0.0150
• Publications: 47 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=-0.71).
• BP6: Variant 20-63689615-T-C is Benign according to our data. Variant chr20-63689615-T-C is described in ClinVar as Benign. ClinVar VariationId is 403398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.015 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.93 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.1992T>C	p.Asp664Asp	synonymous	Exon 23 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.2064T>C	p.Asp688Asp	synonymous	Exon 23 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.1992T>C	p.Asp664Asp	synonymous	Exon 23 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.1992T>C	p.Asp664Asp	synonymous	Exon 23 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.2064T>C	p.Asp688Asp	synonymous	Exon 23 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.1992T>C	p.Asp664Asp	synonymous	Exon 23 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.804 AC: 122186 AN: 152016 Hom.: 50274 Cov.: 32

Gnomad AFR AF: 0.938

Gnomad AMI AF: 0.814

Gnomad AMR AF: 0.772

Gnomad ASJ AF: 0.756

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.725

Gnomad FIN AF: 0.800

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.776

Gnomad OTH AF: 0.797

GnomAD2 exomes AF: 0.742 AC: 184408 AN: 248428 AF XY: 0.743

Gnomad AFR exome AF: 0.943

Gnomad AMR exome AF: 0.737

Gnomad ASJ exome AF: 0.757

Gnomad EAS exome AF: 0.286

Gnomad FIN exome AF: 0.803

Gnomad NFE exome AF: 0.780

Gnomad OTH exome AF: 0.755

GnomAD4 exome AF: 0.756 AC: 1102831 AN: 1459594 Hom.: 422171 Cov.: 52 AF XY: 0.755 AC XY: 548568 AN XY: 726102

African (AFR) AF: 0.950 AC: 31792 AN: 33476

American (AMR) AF: 0.736 AC: 32860 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.759 AC: 19805 AN: 26098

East Asian (EAS) AF: 0.313 AC: 12392 AN: 39650

South Asian (SAS) AF: 0.733 AC: 63217 AN: 86204

European-Finnish (FIN) AF: 0.803 AC: 41836 AN: 52068

Middle Eastern (MID) AF: 0.780 AC: 4492 AN: 5758

European-Non Finnish (NFE) AF: 0.766 AC: 851315 AN: 1111368

Other (OTH) AF: 0.748 AC: 45122 AN: 60316

GnomAD4 genome AF: 0.804 AC: 122308 AN: 152134 Hom.: 50335 Cov.: 32 AF XY: 0.800 AC XY: 59499 AN XY: 74354

African (AFR) AF: 0.938 AC: 38948 AN: 41526

American (AMR) AF: 0.772 AC: 11809 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.756 AC: 2624 AN: 3470

East Asian (EAS) AF: 0.299 AC: 1543 AN: 5156

South Asian (SAS) AF: 0.725 AC: 3498 AN: 4822

European-Finnish (FIN) AF: 0.800 AC: 8475 AN: 10600

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

European-Non Finnish (NFE) AF: 0.776 AC: 52762 AN: 67954

Other (OTH) AF: 0.794 AC: 1672 AN: 2106

Alfa AF: 0.790 Hom.: 86394

Bravo AF: 0.804

Asia WGS AF: 0.551 AC: 1919 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (5)
-	-	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	-0.71
CADD	Benign	0.66
DANN	Benign	0.84
PhyloP100		0.015
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6062302; hg19: chr20-62320968; COSMIC: COSV58894606; COSMIC: COSV58894606;