20-63659394-C-T

Variant names:

• chr20-63659394-C-T
• rs2146141277
• ENST00000492259.6:n.-9C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000492259.6(RTEL1-TNFRSF6B):​n.-9C>T 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 0.00000412 in 1,456,848 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RTEL1-TNFRSF6B ENST00000492259.6 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.14
• Publications: 0 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• dyskeratosis congenita, autosomal recessive 5

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• acute myeloid leukemia

  Inheritance: AD, AR Classification: MODERATE Submitted by: Genomics England PanelApp
• dyskeratosis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hoyeraal-Hreidarsson syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.-9C>T		5_prime_UTR_variant	Exon 2 of 35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTEL1-TNFRSF6B	ENST00000492259.6	n.-9C>T		non_coding_transcript_exon_variant	Exon 1 of 35	5		ENSP00000457428.1
RTEL1	ENST00000360203.11	c.-9C>T		5_prime_UTR_variant	Exon 2 of 35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7	c.-9C>T		5_prime_UTR_variant	Exon 2 of 35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7	c.-9C>T		5_prime_UTR_variant	Exon 2 of 35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6	n.-9C>T		5_prime_UTR_variant	Exon 1 of 35	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1456848 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725164

African (AFR) AF: 0.00 AC: 0 AN: 33374

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000542 AC: 6 AN: 1107494

Other (OTH) AF: 0.00 AC: 0 AN: 60192

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.0
DANN	Benign	0.91
PhyloP100		-1.1

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: rs2146141277; hg19: chr20-62290747;