rs115464632

Variant names:

• chr20-63693189-G-A
• rs115464632
• NM_001283009.2:c.2898G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-63693189-G-A
• chr20-63693189-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001283009.2(RTEL1):​c.2898G>A​(p.Glu966Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000695 in 1,612,176 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000074 (1 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 0.660
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-63693189-G-A is Benign according to our data. Variant chr20-63693189-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 761320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.66 with no splicing effect.

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.2898G>A	p.Glu966Glu	synonymous	Exon 30 of 35	NP_001269938.1
	RTEL1	NM_032957.5		c.2970G>A	p.Glu990Glu	synonymous	Exon 30 of 35	NP_116575.3
	RTEL1	NM_016434.4		c.2898G>A	p.Glu966Glu	synonymous	Exon 30 of 35	NP_057518.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.2898G>A	p.Glu966Glu	synonymous	Exon 30 of 35	ENSP00000353332.5
	RTEL1	ENST00000508582.7	TSL:2	c.2970G>A	p.Glu990Glu	synonymous	Exon 30 of 35	ENSP00000424307.2
	RTEL1	ENST00000370018.7	TSL:1	c.2898G>A	p.Glu966Glu	synonymous	Exon 30 of 35	ENSP00000359035.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152072 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000642 AC: 16 AN: 249374 AF XY: 0.0000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000740 AC: 108 AN: 1459986 Hom.: 1 Cov.: 33 AF XY: 0.0000730 AC XY: 53 AN XY: 726290

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00242 AC: 96 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52074

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111582

Other (OTH) AF: 0.0000663 AC: 4 AN: 60338

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74408

African (AFR) AF: 0.00 AC: 0 AN: 41506

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.74
PhyloP100		0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

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: rs115464632; hg19: chr20-62324542;