rs398123050

Variant names:

• chr20-63689870-G-A
• rs398123050
• NM_001283009.2:c.2141+5G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-63689870-G-A
• chr20-63689870-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001283009.2(RTEL1):​c.2141+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,451,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: RTEL1 NM_001283009.2 splice_region, intron
• Scores: Splicing: ADA: 0.9848
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 0.0260
• Publications: 2 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-63689870-G-A is Pathogenic according to our data. Variant chr20-63689870-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 65415.

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.2141+5G>A		splice_region intron	N/A	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.2213+5G>A		splice_region intron	N/A	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.2141+5G>A		splice_region 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.2141+5G>A		splice_region intron	N/A	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.2213+5G>A		splice_region intron	N/A	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.2141+5G>A		splice_region intron	N/A	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000418 AC: 1 AN: 239234 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000551

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1451744 Hom.: 0 Cov.: 34 AF XY: 0.00000415 AC XY: 3 AN XY: 722562

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1109544

Other (OTH) AF: 0.00 AC: 0 AN: 60202

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	1	-	Dyskeratosis congenita, autosomal recessive 5 (4)
-	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	-0.82
CADD	Benign	20
DANN	Benign	0.66
PhyloP100		0.026
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs398123050; hg19: chr20-62321223;