chr20-63688003-C-T

Variant names:

• chr20-63688003-C-T
• rs116057134
• NM_001283009.2:c.1548C>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.1548C>T​(p.Val516Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000708 in 1,612,822 control chromosomes in the GnomAD database, including 6 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. V516V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (3 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.309
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 20-63688003-C-T is Benign according to our data. Variant chr20-63688003-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 540948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.309 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00401 (611/152352) while in subpopulation AFR AF = 0.0139 (578/41580). AF 95% confidence interval is 0.013. There are 3 homozygotes in GnomAd4. There are 287 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.1548C>T	p.Val516Val	synonymous	Exon 18 of 35	NP_001269938.1
	RTEL1	NM_032957.5		c.1620C>T	p.Val540Val	synonymous	Exon 18 of 35	NP_116575.3
	RTEL1	NM_016434.4		c.1548C>T	p.Val516Val	synonymous	Exon 18 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.1548C>T	p.Val516Val	synonymous	Exon 18 of 35	ENSP00000353332.5
	RTEL1	ENST00000508582.7	TSL:2	c.1620C>T	p.Val540Val	synonymous	Exon 18 of 35	ENSP00000424307.2
	RTEL1	ENST00000370018.7	TSL:1	c.1548C>T	p.Val516Val	synonymous	Exon 18 of 35	ENSP00000359035.3

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 609 AN: 152234 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000998 AC: 249 AN: 249444 AF XY: 0.000708

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000364 AC: 531 AN: 1460470 Hom.: 3 Cov.: 33 AF XY: 0.000300 AC XY: 218 AN XY: 726522

African (AFR) AF: 0.0135 AC: 453 AN: 33480

American (AMR) AF: 0.000649 AC: 29 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52074

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111964

Other (OTH) AF: 0.000596 AC: 36 AN: 60376

GnomAD4 genome AF: 0.00401 AC: 611 AN: 152352 Hom.: 3 Cov.: 33 AF XY: 0.00385 AC XY: 287 AN XY: 74506

African (AFR) AF: 0.0139 AC: 578 AN: 41580

American (AMR) AF: 0.00170 AC: 26 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00198 Hom.: 1

Bravo AF: 0.00415

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.1
DANN	Benign	0.76
PhyloP100		0.31
PromoterAI		-0.0036	Neutral
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)		0.030		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: rs116057134; hg19: chr20-62319356;