rs2297440

Variant names:

• chr20-63680946-T-C
• rs2297440
• NM_001283009.2:c.1191+227T>C

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.1191+227T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.767 in 985,136 control chromosomes in the GnomAD database, including 292,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (50346 hom., cov: 32)
  • Exomes 𝑓: 0.76 (241915 hom.)
• Consequence: RTEL1 NM_001283009.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.362
• Publications: 55 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=-0.91).
• BP6: Variant 20-63680946-T-C is Benign according to our data. Variant chr20-63680946-T-C is described in ClinVar as Benign. ClinVar VariationId is 1224071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.931 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.1191+227T>C		intron	N/A	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.1263+227T>C		intron	N/A	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.1191+227T>C		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.1191+227T>C		intron	N/A	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.1263+227T>C		intron	N/A	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.1191+227T>C		intron	N/A	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.804 AC: 122164 AN: 151996 Hom.: 50285 Cov.: 32

Gnomad AFR AF: 0.938

Gnomad AMI AF: 0.815

Gnomad AMR AF: 0.771

Gnomad ASJ AF: 0.751

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.800

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.777

Gnomad OTH AF: 0.796

GnomAD4 exome AF: 0.760 AC: 633479 AN: 833022 Hom.: 241915 Cov.: 39 AF XY: 0.761 AC XY: 292584 AN XY: 384682

African (AFR) AF: 0.957 AC: 15103 AN: 15786

American (AMR) AF: 0.700 AC: 689 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.753 AC: 3881 AN: 5152

East Asian (EAS) AF: 0.276 AC: 1003 AN: 3630

South Asian (SAS) AF: 0.746 AC: 12272 AN: 16458

European-Finnish (FIN) AF: 0.775 AC: 214 AN: 276

Middle Eastern (MID) AF: 0.766 AC: 1240 AN: 1618

European-Non Finnish (NFE) AF: 0.760 AC: 578920 AN: 761822

Other (OTH) AF: 0.738 AC: 20157 AN: 27296

GnomAD4 genome AF: 0.804 AC: 122288 AN: 152114 Hom.: 50346 Cov.: 32 AF XY: 0.800 AC XY: 59494 AN XY: 74346

African (AFR) AF: 0.938 AC: 38955 AN: 41514

American (AMR) AF: 0.771 AC: 11785 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.751 AC: 2603 AN: 3468

East Asian (EAS) AF: 0.290 AC: 1495 AN: 5154

South Asian (SAS) AF: 0.729 AC: 3513 AN: 4820

European-Finnish (FIN) AF: 0.800 AC: 8470 AN: 10594

Middle Eastern (MID) AF: 0.806 AC: 237 AN: 294

European-Non Finnish (NFE) AF: 0.777 AC: 52815 AN: 67962

Other (OTH) AF: 0.794 AC: 1673 AN: 2108

Alfa AF: 0.777 Hom.: 35624

Bravo AF: 0.804

Asia WGS AF: 0.550 AC: 1916 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.47
DANN	Benign	0.58
PhyloP100		-0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2297440; hg19: chr20-62312299; COSMIC: COSV107378209; COSMIC: COSV107378209;