Genetic Variant NM_001283009.2:c.2313_2315delAGA (chr20-63690337-GAGA-G) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_SupportingBP6_Very_StrongBS1BS2

The NM_001283009.2(RTEL1):c.2313_2315delAGA(p.Glu771del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,610,860 control chromosomes in the GnomAD database, including 30 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0053 ( 27 hom. )

Consequence

RTEL1
NM_001283009.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.71

Publications

2 publications found

Variant links:

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 links:

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]

RTEL1-TNFRSF6B links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001283009.2. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 20-63690337-GAGA-G is Benign according to our data. Variant chr20-63690337-GAGA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00483 (736/152298) while in subpopulation NFE AF = 0.00609 (414/68002). AF 95% confidence interval is 0.0056. There are 3 homozygotes in GnomAd4. There are 378 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RTEL1	NM_001283009.2	MANE Select	c.2313_2315delAGA	p.Glu771del	disruptive_inframe_deletion	Exon 26 of 35	NP_001269938.1	Q9NZ71-6
RTEL1	NM_032957.5		c.2385_2387delAGA	p.Glu795del	disruptive_inframe_deletion	Exon 26 of 35	NP_116575.3	Q9NZ71-7
RTEL1	NM_016434.4		c.2313_2315delAGA	p.Glu771del	disruptive_inframe_deletion	Exon 26 of 35	NP_057518.1	Q9NZ71-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.2313_2315delAGA	p.Glu771del	disruptive_inframe_deletion	Exon 26 of 35	ENSP00000353332.5	Q9NZ71-6
RTEL1	ENST00000508582.7	TSL:2	c.2385_2387delAGA	p.Glu795del	disruptive_inframe_deletion	Exon 26 of 35	ENSP00000424307.2	Q9NZ71-7
RTEL1	ENST00000370018.7	TSL:1	c.2313_2315delAGA	p.Glu771del	disruptive_inframe_deletion	Exon 26 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes

AF:

0.00484

AC:

737

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00582

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.0158

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00609

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00555

AC:

1379

AN:

248682

AF XY:

0.00538

show subpopulations

Gnomad AFR exome

AF:

0.000748

Gnomad AMR exome

AF:

0.00407

Gnomad ASJ exome

AF:

0.00182

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0160

Gnomad NFE exome

AF:

0.00708

Gnomad OTH exome

AF:

0.00495

GnomAD4 exome

AF:

0.00528

AC:

7695

AN:

1458562

Hom.:

AF XY:

0.00510

AC XY:

3701

AN XY:

725464

show subpopulations

African (AFR)

AF:

0.000628

AC:

AN:

33426

American (AMR)

AF:

0.00399

AC:

178

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.00257

AC:

AN:

26042

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.00124

AC:

107

AN:

86160

European-Finnish (FIN)

AF:

0.0166

AC:

861

AN:

51914

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00552

AC:

6126

AN:

1110786

Other (OTH)

AF:

0.00538

AC:

324

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

404

807

1211

1614

2018

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

202

404

606

808

1010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00483

AC:

736

AN:

152298

Hom.:

Cov.:

AF XY:

0.00508

AC XY:

378

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41562

American (AMR)

AF:

0.00582

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000621

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0158

AC:

168

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00609

AC:

414

AN:

68002

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

118

158

197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00585

Hom.:

Bravo

AF:

0.00381

EpiCase

AF:

0.00567

EpiControl

AF:

0.00605

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (1)

not specified (1)

RTEL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.7

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over