20-63659344-A-C

Position:

• chr20-63659344-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001283009.2(RTEL1):​c.-59A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0537 in 1,320,270 control chromosomes in the GnomAD database, including 2,369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (172 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2197 hom.)
• Consequence: RTEL1 NM_001283009.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.119

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-63659344-A-C is Benign according to our data. Variant chr20-63659344-A-C is described in ClinVar as [Benign]. Clinvar id is 1279544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63659344-A-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.-59A>C		5_prime_UTR_variant	2/35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203	c.-59A>C		5_prime_UTR_variant	2/35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582	c.-59A>C		5_prime_UTR_variant	2/35	2		ENSP00000424307.2
RTEL1	ENST00000370018	c.-59A>C		5_prime_UTR_variant	2/35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6	n.-59A>C		non_coding_transcript_exon_variant	1/35	5		ENSP00000457428.1
RTEL1-TNFRSF6B	ENST00000492259	n.-59A>C		5_prime_UTR_variant	1/34	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes AF: 0.0386 AC: 5873 AN: 152122 Hom.: 172 Cov.: 33

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0174

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00850

Gnomad FIN AF: 0.0596

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0622

Gnomad OTH AF: 0.0298

GnomAD4 exome AF: 0.0557 AC: 65023 AN: 1168030 Hom.: 2197 Cov.: 16 AF XY: 0.0537 AC XY: 31875 AN XY: 593646

Gnomad4 AFR exome AF: 0.00875

Gnomad4 AMR exome AF: 0.0143

Gnomad4 ASJ exome AF: 0.0213

Gnomad4 EAS exome AF: 0.000261

Gnomad4 SAS exome AF: 0.00952

Gnomad4 FIN exome AF: 0.0579

Gnomad4 NFE exome AF: 0.0679

Gnomad4 OTH exome AF: 0.0465

GnomAD4 genome AF: 0.0386 AC: 5870 AN: 152240 Hom.: 172 Cov.: 33 AF XY: 0.0369 AC XY: 2748 AN XY: 74424

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.0173

Gnomad4 ASJ AF: 0.0242

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00830

Gnomad4 FIN AF: 0.0596

Gnomad4 NFE AF: 0.0622

Gnomad4 OTH AF: 0.0295

Alfa AF: 0.0514 Hom.: 112

Bravo AF: 0.0346

Asia WGS AF: 0.00953 AC: 34 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.0
DANN	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs13043797; hg19: chr20-62290697; COSMIC: COSV58892799; COSMIC: COSV58892799;