20-63692939-C-T

Variant names:

• chr20-63692939-C-T
• rs115030322
• NM_001283009.2:c.2787C>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.2787C>T​(p.Ala929Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000428 in 1,612,638 control chromosomes in the GnomAD database, including 3 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. A929A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00086 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (2 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.50
• 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=-0.72).
• BP6: Variant 20-63692939-C-T is Benign according to our data. Variant chr20-63692939-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 540943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,SD,AR 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.2787C>T	p.Ala929Ala	synonymous	Exon 29 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.2859C>T	p.Ala953Ala	synonymous	Exon 29 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.2787C>T	p.Ala929Ala	synonymous	Exon 29 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.2787C>T	p.Ala929Ala	synonymous	Exon 29 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.2859C>T	p.Ala953Ala	synonymous	Exon 29 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.2787C>T	p.Ala929Ala	synonymous	Exon 29 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152234 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000605 AC: 151 AN: 249778 AF XY: 0.000671

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00223

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000240

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000383 AC: 559 AN: 1460286 Hom.: 2 Cov.: 32 AF XY: 0.000443 AC XY: 322 AN XY: 726438

African (AFR) AF: 0.00200 AC: 67 AN: 33480

American (AMR) AF: 0.000358 AC: 16 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.00156 AC: 62 AN: 39700

South Asian (SAS) AF: 0.00139 AC: 120 AN: 86256

European-Finnish (FIN) AF: 0.0000384 AC: 2 AN: 52082

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.000229 AC: 255 AN: 1111806

Other (OTH) AF: 0.000447 AC: 27 AN: 60360

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152352 Hom.: 1 Cov.: 33 AF XY: 0.000926 AC XY: 69 AN XY: 74496

African (AFR) AF: 0.00202 AC: 84 AN: 41574

American (AMR) AF: 0.000392 AC: 6 AN: 15310

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

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5188

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4834

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000392 Hom.: 0

Bravo AF: 0.000861

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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 provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.1
DANN	Benign	0.67
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs115030322; hg19: chr20-62324292; COSMIC: COSV100541961; COSMIC: COSV100541961;