chr20-63696229-G-A

Variant names:

• chr20-63696229-G-A
• rs2297441
• ENST00000496816.5:n.*1255G>A

Variant summary

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

The ENST00000496816.5(RTEL1):​n.*1255G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.773 in 316,230 control chromosomes in the GnomAD database, including 97,176 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 0.80 (50347 hom., cov: 33)
  • Exomes 𝑓: 0.74 (46829 hom.)
• Consequence: RTEL1 ENST00000496816.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.366
• Publications: 78 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.*371G>A		3_prime_UTR_variant	Exon 35 of 35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11	c.*371G>A		3_prime_UTR_variant	Exon 35 of 35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7	c.*444G>A		3_prime_UTR_variant	Exon 35 of 35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7	c.*444G>A		3_prime_UTR_variant	Exon 35 of 35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6	n.*1331+375G>A		intron_variant	Intron 32 of 34	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes AF: 0.805 AC: 122365 AN: 152056 Hom.: 50291 Cov.: 33

Gnomad AFR AF: 0.936

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.790

Gnomad ASJ AF: 0.769

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.735

Gnomad FIN AF: 0.798

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.770

Gnomad OTH AF: 0.805

GnomAD4 exome AF: 0.744 AC: 122059 AN: 164056 Hom.: 46829 Cov.: 0 AF XY: 0.744 AC XY: 62394 AN XY: 83880

African (AFR) AF: 0.940 AC: 4743 AN: 5044

American (AMR) AF: 0.771 AC: 5166 AN: 6702

Ashkenazi Jewish (ASJ) AF: 0.776 AC: 4412 AN: 5686

East Asian (EAS) AF: 0.363 AC: 4382 AN: 12080

South Asian (SAS) AF: 0.735 AC: 8710 AN: 11850

European-Finnish (FIN) AF: 0.798 AC: 7984 AN: 10000

Middle Eastern (MID) AF: 0.789 AC: 631 AN: 800

European-Non Finnish (NFE) AF: 0.769 AC: 78082 AN: 101526

Other (OTH) AF: 0.767 AC: 7949 AN: 10368

GnomAD4 genome AF: 0.805 AC: 122483 AN: 152174 Hom.: 50347 Cov.: 33 AF XY: 0.802 AC XY: 59675 AN XY: 74394

African (AFR) AF: 0.936 AC: 38916 AN: 41570

American (AMR) AF: 0.790 AC: 12072 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 2669 AN: 3470

East Asian (EAS) AF: 0.358 AC: 1851 AN: 5164

South Asian (SAS) AF: 0.735 AC: 3545 AN: 4820

European-Finnish (FIN) AF: 0.798 AC: 8448 AN: 10584

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.770 AC: 52353 AN: 67962

Other (OTH) AF: 0.802 AC: 1695 AN: 2114

Alfa AF: 0.804 Hom.: 13939

Bravo AF: 0.807

Asia WGS AF: 0.591 AC: 2057 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.8
DANN	Benign	0.82
PhyloP100		0.37
PromoterAI		0.0041	Neutral
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: rs2297441; hg19: chr20-62327582;