20-63667320-C-G

Variant names:

• chr20-63667320-C-G
• rs7261546
• NM_001283009.2:c.615-149C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001283009.2(RTEL1):​c.615-149C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 685,916 control chromosomes in the GnomAD database, including 19,072 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4808 hom., cov: 31)
  • Exomes 𝑓: 0.21 (14264 hom.)
• Consequence: RTEL1 NM_001283009.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.30
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 20-63667320-C-G is Benign according to our data. Variant chr20-63667320-C-G is described in ClinVar as Benign. ClinVar VariationId is 1184808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.338 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.615-149C>G		intron	N/A	NP_001269938.1
	RTEL1	NM_032957.5		c.687-149C>G		intron	N/A	NP_116575.3
	RTEL1	NM_016434.4		c.615-149C>G		intron	N/A	NP_057518.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.615-149C>G		intron	N/A	ENSP00000353332.5
	RTEL1	ENST00000508582.7	TSL:2	c.687-149C>G		intron	N/A	ENSP00000424307.2
	RTEL1	ENST00000370018.7	TSL:1	c.615-149C>G		intron	N/A	ENSP00000359035.3

Frequencies

GnomAD3 genomes AF: 0.237 AC: 35973 AN: 151904 Hom.: 4796 Cov.: 31

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.255

GnomAD4 exome AF: 0.214 AC: 114392 AN: 533894 Hom.: 14264 AF XY: 0.219 AC XY: 62707 AN XY: 286424

African (AFR) AF: 0.336 AC: 5304 AN: 15766

American (AMR) AF: 0.389 AC: 12973 AN: 33350

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 3478 AN: 16286

East Asian (EAS) AF: 0.154 AC: 5200 AN: 33768

South Asian (SAS) AF: 0.340 AC: 19748 AN: 58114

European-Finnish (FIN) AF: 0.133 AC: 5288 AN: 39828

Middle Eastern (MID) AF: 0.253 AC: 934 AN: 3696

European-Non Finnish (NFE) AF: 0.182 AC: 55304 AN: 304152

Other (OTH) AF: 0.213 AC: 6163 AN: 28934

GnomAD4 genome AF: 0.237 AC: 36023 AN: 152022 Hom.: 4808 Cov.: 31 AF XY: 0.236 AC XY: 17560 AN XY: 74348

African (AFR) AF: 0.324 AC: 13427 AN: 41416

American (AMR) AF: 0.314 AC: 4787 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 734 AN: 3470

East Asian (EAS) AF: 0.152 AC: 786 AN: 5160

South Asian (SAS) AF: 0.352 AC: 1700 AN: 4824

European-Finnish (FIN) AF: 0.117 AC: 1239 AN: 10596

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12561 AN: 67978

Other (OTH) AF: 0.259 AC: 546 AN: 2108

Alfa AF: 0.0609 Hom.: 65

Bravo AF: 0.254

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Dyskeratosis congenita, autosomal recessive 5 (1)
-	-	1	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.1
DANN	Benign	0.51
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs7261546; hg19: chr20-62298673; COSMIC: COSV58893296; COSMIC: COSV58893296;