20-63678326-C-T

Variant names:

• chr20-63678326-C-T
• rs35877957
• NM_001283009.2:c.1017C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001283009.2(RTEL1):​c.1017C>T​(p.Ser339Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,612,540 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0058 (33 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.884
• 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]

LOC124904954 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 20-63678326-C-T is Benign according to our data. Variant chr20-63678326-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.884 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00343 (522/152240) while in subpopulation NFE AF = 0.00638 (434/68016). AF 95% confidence interval is 0.00589. There are 1 homozygotes in GnomAd4. There are 215 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 33 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.1017C>T	p.Ser339Ser	synonymous	Exon 12 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.1089C>T	p.Ser363Ser	synonymous	Exon 12 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.1017C>T	p.Ser339Ser	synonymous	Exon 12 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.1017C>T	p.Ser339Ser	synonymous	Exon 12 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.1089C>T	p.Ser363Ser	synonymous	Exon 12 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.1017C>T	p.Ser339Ser	synonymous	Exon 12 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.00343 AC: 522 AN: 152122 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00638

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00353 AC: 874 AN: 247720 AF XY: 0.00365

Gnomad AFR exome AF: 0.000496

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.000803

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000782

Gnomad NFE exome AF: 0.00638

Gnomad OTH exome AF: 0.00513

GnomAD4 exome AF: 0.00578 AC: 8438 AN: 1460300 Hom.: 33 Cov.: 36 AF XY: 0.00566 AC XY: 4114 AN XY: 726434

African (AFR) AF: 0.000508 AC: 17 AN: 33464

American (AMR) AF: 0.00226 AC: 101 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.000919 AC: 24 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000882 AC: 76 AN: 86156

European-Finnish (FIN) AF: 0.00101 AC: 53 AN: 52550

Middle Eastern (MID) AF: 0.00211 AC: 12 AN: 5680

European-Non Finnish (NFE) AF: 0.00707 AC: 7861 AN: 1111674

Other (OTH) AF: 0.00487 AC: 294 AN: 60336

GnomAD4 genome AF: 0.00343 AC: 522 AN: 152240 Hom.: 1 Cov.: 31 AF XY: 0.00289 AC XY: 215 AN XY: 74436

African (AFR) AF: 0.00111 AC: 46 AN: 41548

American (AMR) AF: 0.00144 AC: 22 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00638 AC: 434 AN: 68016

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00400 Hom.: 3

Bravo AF: 0.00345

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00562

EpiControl AF: 0.00682

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.061
DANN	Benign	0.72
PhyloP100		-0.88
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs35877957; hg19: chr20-62309679; COSMIC: COSV58893982; COSMIC: COSV58893982;