20-63695773-C-G

Variant names:

• chr20-63695773-C-G
• rs141522376
• NM_001283009.2:c.3823-5C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001283009.2(RTEL1):​c.3823-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,590,056 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (16 hom.)
• Consequence: RTEL1 NM_001283009.2 splice_region, intron
• Scores: Splicing: ADA: 0.001674
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0460
• Publications: 1 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=-0.6).
• BP6: Variant 20-63695773-C-G is Benign according to our data. Variant chr20-63695773-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00232 (353/152318) while in subpopulation NFE AF = 0.00387 (263/68006). AF 95% confidence interval is 0.00348. There are 3 homozygotes in GnomAd4. There are 149 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	NM_001283009.2	MANE Select	c.3823-5C>G		splice_region intron	N/A	NP_001269938.1
	RTEL1	NM_032957.5		c.3725-5C>G		splice_region intron	N/A	NP_116575.3
	RTEL1	NM_016434.4		c.3653-5C>G		splice_region intron	N/A	NP_057518.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.3823-5C>G		splice_region intron	N/A	ENSP00000353332.5
	RTEL1	ENST00000508582.7	TSL:2	c.3725-5C>G		splice_region intron	N/A	ENSP00000424307.2
	RTEL1	ENST00000370018.7	TSL:1	c.3653-5C>G		splice_region intron	N/A	ENSP00000359035.3

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 352 AN: 152200 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00387

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00271 AC: 563 AN: 207454 AF XY: 0.00272

Gnomad AFR exome AF: 0.000614

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000631

Gnomad FIN exome AF: 0.00172

Gnomad NFE exome AF: 0.00484

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00410 AC: 5895 AN: 1437738 Hom.: 16 Cov.: 33 AF XY: 0.00397 AC XY: 2835 AN XY: 713382

African (AFR) AF: 0.000544 AC: 18 AN: 33118

American (AMR) AF: 0.00227 AC: 92 AN: 40616

Ashkenazi Jewish (ASJ) AF: 0.0000390 AC: 1 AN: 25656

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38626

South Asian (SAS) AF: 0.0000598 AC: 5 AN: 83600

European-Finnish (FIN) AF: 0.00157 AC: 79 AN: 50250

Middle Eastern (MID) AF: 0.000716 AC: 4 AN: 5590

European-Non Finnish (NFE) AF: 0.00497 AC: 5472 AN: 1100862

Other (OTH) AF: 0.00375 AC: 223 AN: 59420

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152318 Hom.: 3 Cov.: 33 AF XY: 0.00200 AC XY: 149 AN XY: 74484

African (AFR) AF: 0.00101 AC: 42 AN: 41570

American (AMR) AF: 0.00196 AC: 30 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00387 AC: 263 AN: 68006

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00273 Hom.: 1

Bravo AF: 0.00266

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Dyskeratosis congenita (2)
-	-	2	not specified (2)
-	-	1	Dyskeratosis congenita, autosomal recessive 5;C4225346: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	-0.60
CADD	Benign	7.1
DANN	Benign	0.76
PhyloP100		0.046
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0017
dbscSNV1_RF	Benign	0.096
SpliceAI score (max)		0.15		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: rs141522376; hg19: chr20-62327126;