20-63692813-C-T

Variant names:

• chr20-63692813-C-T
• rs3848671
• NM_001283009.2:c.2661C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001283009.2(RTEL1):​c.2661C>T​(p.Pro887Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,610,740 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P887P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.65
• Publications: 2 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 20-63692813-C-T is Benign according to our data. Variant chr20-63692813-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 540950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.65 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.2661C>T	p.Pro887Pro	synonymous	Exon 29 of 35	NP_001269938.1
	RTEL1	NM_032957.5		c.2733C>T	p.Pro911Pro	synonymous	Exon 29 of 35	NP_116575.3
	RTEL1	NM_016434.4		c.2661C>T	p.Pro887Pro	synonymous	Exon 29 of 35	NP_057518.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.2661C>T	p.Pro887Pro	synonymous	Exon 29 of 35	ENSP00000353332.5
	RTEL1	ENST00000508582.7	TSL:2	c.2733C>T	p.Pro911Pro	synonymous	Exon 29 of 35	ENSP00000424307.2
	RTEL1	ENST00000370018.7	TSL:1	c.2661C>T	p.Pro887Pro	synonymous	Exon 29 of 35	ENSP00000359035.3

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 171 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00114 AC: 284 AN: 248680 AF XY: 0.000961

Gnomad AFR exome AF: 0.000625

Gnomad AMR exome AF: 0.00307

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.00158 AC: 2298 AN: 1458424 Hom.: 4 Cov.: 30 AF XY: 0.00151 AC XY: 1094 AN XY: 725168

African (AFR) AF: 0.000837 AC: 28 AN: 33434

American (AMR) AF: 0.00296 AC: 132 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26112

East Asian (EAS) AF: 0.000757 AC: 30 AN: 39622

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86218

European-Finnish (FIN) AF: 0.000192 AC: 10 AN: 52056

Middle Eastern (MID) AF: 0.000359 AC: 2 AN: 5578

European-Non Finnish (NFE) AF: 0.00180 AC: 1995 AN: 1110506

Other (OTH) AF: 0.00136 AC: 82 AN: 60232

GnomAD4 genome AF: 0.00112 AC: 171 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.000994 AC XY: 74 AN XY: 74478

African (AFR) AF: 0.000770 AC: 32 AN: 41560

American (AMR) AF: 0.00118 AC: 18 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5188

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00156 AC: 106 AN: 68026

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.00112

EpiCase AF: 0.000491

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Dyskeratosis congenita (2)
-	-	1	Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	RTEL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.067
DANN	Benign	0.75
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs3848671; hg19: chr20-62324166; COSMIC: COSV104623456; COSMIC: COSV104623456;