chr20-63686867-T-C

Variant names:

• chr20-63686867-T-C
• rs4809324
• NM_001283009.2:c.1349-771T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001283009.2(RTEL1):​c.1349-771T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0918 in 166,520 control chromosomes in the GnomAD database, including 994 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.091 (914 hom., cov: 33)
  • Exomes 𝑓: 0.10 (80 hom.)
• Consequence: RTEL1 NM_001283009.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60
• Publications: 67 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

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.1349-771T>C		intron	N/A	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.1421-771T>C		intron	N/A	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.1349-771T>C		intron	N/A	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.1349-771T>C		intron	N/A	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.1421-771T>C		intron	N/A	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.1349-771T>C		intron	N/A	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.0908 AC: 13800 AN: 151974 Hom.: 904 Cov.: 33

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.0591

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0583

Gnomad MID AF: 0.0701

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.107

GnomAD4 exome AF: 0.101 AC: 1451 AN: 14428 Hom.: 80 Cov.: 0 AF XY: 0.0999 AC XY: 761 AN XY: 7616

African (AFR) AF: 0.0191 AC: 6 AN: 314

American (AMR) AF: 0.250 AC: 76 AN: 304

Ashkenazi Jewish (ASJ) AF: 0.0547 AC: 22 AN: 402

East Asian (EAS) AF: 0.153 AC: 259 AN: 1698

South Asian (SAS) AF: 0.0847 AC: 10 AN: 118

European-Finnish (FIN) AF: 0.0640 AC: 112 AN: 1750

Middle Eastern (MID) AF: 0.0735 AC: 5 AN: 68

European-Non Finnish (NFE) AF: 0.0977 AC: 884 AN: 9048

Other (OTH) AF: 0.106 AC: 77 AN: 726

GnomAD4 genome AF: 0.0909 AC: 13828 AN: 152092 Hom.: 914 Cov.: 33 AF XY: 0.0900 AC XY: 6695 AN XY: 74368

African (AFR) AF: 0.0251 AC: 1043 AN: 41526

American (AMR) AF: 0.204 AC: 3114 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0591 AC: 205 AN: 3470

East Asian (EAS) AF: 0.134 AC: 689 AN: 5154

South Asian (SAS) AF: 0.105 AC: 504 AN: 4820

European-Finnish (FIN) AF: 0.0583 AC: 619 AN: 10612

Middle Eastern (MID) AF: 0.0685 AC: 20 AN: 292

European-Non Finnish (NFE) AF: 0.108 AC: 7325 AN: 67920

Other (OTH) AF: 0.113 AC: 238 AN: 2114

Alfa AF: 0.108 Hom.: 4179

Bravo AF: 0.102

Asia WGS AF: 0.129 AC: 448 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.5
DANN	Benign	0.65
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs4809324; hg19: chr20-62318220;