rs863225053

Variant names:

• chr20-63690161-GCCATGTCAT-G
• rs863225053
• NM_001283009.2:c.2219_2227delATGTCATCC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PM4 PP5_Very_Strong

The NM_001283009.2(RTEL1):​c.2219_2227delATGTCATCC​(p.His740_Ile742del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. H740H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RTEL1 NM_001283009.2 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.99
• 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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001283009.2.
• PP5: Variant 20-63690161-GCCATGTCAT-G is Pathogenic according to our data. Variant chr20-63690161-GCCATGTCAT-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217283.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	NM_001283009.2	MANE Select	c.2219_2227delATGTCATCC	p.His740_Ile742del	disruptive_inframe_deletion	Exon 25 of 35	NP_001269938.1
	RTEL1	NM_032957.5		c.2291_2299delATGTCATCC	p.His764_Ile766del	disruptive_inframe_deletion	Exon 25 of 35	NP_116575.3
	RTEL1	NM_016434.4		c.2219_2227delATGTCATCC	p.His740_Ile742del	disruptive_inframe_deletion	Exon 25 of 35	NP_057518.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.2219_2227delATGTCATCC	p.His740_Ile742del	disruptive_inframe_deletion	Exon 25 of 35	ENSP00000353332.5
	RTEL1	ENST00000508582.7	TSL:2	c.2291_2299delATGTCATCC	p.His764_Ile766del	disruptive_inframe_deletion	Exon 25 of 35	ENSP00000424307.2
	RTEL1	ENST00000370018.7	TSL:1	c.2219_2227delATGTCATCC	p.His740_Ile742del	disruptive_inframe_deletion	Exon 25 of 35	ENSP00000359035.3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Interstitial lung disease 2 (1)
1	-	-	not provided (1)
1	-	-	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs863225053; hg19: chr20-62321514;