NM_001283009.2:c.1482-1G>A

Variant names:

• chr20-63687936-G-A
• rs863225129
• NM_001283009.2:c.1482-1G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_001283009.2(RTEL1):​c.1482-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000685 in 1,460,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: RTEL1 NM_001283009.2 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.67
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0292083 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.1, offset of 11, new splice context is: cacgctcaaccctttcccAGtct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP5: Variant 20-63687936-G-A is Pathogenic according to our data. Variant chr20-63687936-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1482-1G>A		splice_acceptor intron	N/A	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.1554-1G>A		splice_acceptor intron	N/A	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.1482-1G>A		splice_acceptor 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.1482-1G>A		splice_acceptor intron	N/A	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.1554-1G>A		splice_acceptor intron	N/A	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.1482-1G>A		splice_acceptor intron	N/A	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460204 Hom.: 0 Cov.: 33 AF XY: 0.00000826 AC XY: 6 AN XY: 726394

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111744

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000108 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Dyskeratosis congenita (1)
1	-	-	Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (1)
1	-	-	Interstitial lung disease 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		6.7
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.80		Position offset: 12
DS_AL_spliceai		0.96		Position offset: 1

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

Other links and lift over

dbSNP: rs863225129; hg19: chr20-62319289; COSMIC: COSV58893789; COSMIC: COSV58893789;