rs61753459

Variant names:

• chr20-63689836-C-T
• rs61753459
• NM_001283009.2:c.2112C>T
• RTEL1 p.Asp704Asp

Your query was ambiguous. Multiple possible variants found:

• chr20-63689836-C-T
• chr20-63689836-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001283009.2(RTEL1):​c.2112C>T​(p.Asp704Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0818 in 1,610,866 control chromosomes in the GnomAD database, including 6,074 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (419 hom., cov: 33)
  • Exomes 𝑓: 0.083 (5655 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.634
• Publications: 12 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 20-63689836-C-T is Benign according to our data. Variant chr20-63689836-C-T is described in ClinVar as Benign. ClinVar VariationId is 403399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.634 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.114 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.2112C>T	p.Asp704Asp	synonymous	Exon 24 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.2184C>T	p.Asp728Asp	synonymous	Exon 24 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.2112C>T	p.Asp704Asp	synonymous	Exon 24 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.2112C>T	p.Asp704Asp	synonymous	Exon 24 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.2184C>T	p.Asp728Asp	synonymous	Exon 24 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.2112C>T	p.Asp704Asp	synonymous	Exon 24 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.0666 AC: 10130 AN: 152142 Hom.: 420 Cov.: 33

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0796

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0809

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0904

Gnomad OTH AF: 0.0842

GnomAD2 exomes AF: 0.0791 AC: 19445 AN: 245828 AF XY: 0.0845

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.0572

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.000273

Gnomad FIN exome AF: 0.0850

Gnomad NFE exome AF: 0.0914

Gnomad OTH exome AF: 0.0959

GnomAD4 exome AF: 0.0834 AC: 121616 AN: 1458606 Hom.: 5655 Cov.: 36 AF XY: 0.0859 AC XY: 62320 AN XY: 725660

African (AFR) AF: 0.0146 AC: 489 AN: 33474

American (AMR) AF: 0.0608 AC: 2717 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 3149 AN: 26106

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39684

South Asian (SAS) AF: 0.123 AC: 10605 AN: 86244

European-Finnish (FIN) AF: 0.0850 AC: 4305 AN: 50676

Middle Eastern (MID) AF: 0.143 AC: 825 AN: 5760

European-Non Finnish (NFE) AF: 0.0850 AC: 94515 AN: 1111622

Other (OTH) AF: 0.0829 AC: 5001 AN: 60344

GnomAD4 genome AF: 0.0665 AC: 10132 AN: 152260 Hom.: 419 Cov.: 33 AF XY: 0.0671 AC XY: 4999 AN XY: 74448

African (AFR) AF: 0.0165 AC: 684 AN: 41564

American (AMR) AF: 0.0795 AC: 1217 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 395 AN: 3470

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5182

South Asian (SAS) AF: 0.122 AC: 590 AN: 4828

European-Finnish (FIN) AF: 0.0809 AC: 859 AN: 10618

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0904 AC: 6148 AN: 67976

Other (OTH) AF: 0.0833 AC: 176 AN: 2112

Alfa AF: 0.0749 Hom.: 458

Bravo AF: 0.0610

Asia WGS AF: 0.0450 AC: 156 AN: 3478

EpiCase AF: 0.0951

EpiControl AF: 0.0984

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	2	not specified (2)
-	-	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	-0.41
CADD	Benign	17
DANN	Benign	0.95
PhyloP100		0.63
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61753459;

hg19: chr20-62321189;

COSMIC: COSV58893451;

COSMIC: COSV58893451;