chr20-63687931-G-A

Variant names:

• chr20-63687931-G-A
• rs76364377
• NM_001283009.2:c.1482-6G>A

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.1482-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0624 in 1,612,066 control chromosomes in the GnomAD database, including 3,568 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (244 hom., cov: 33)
  • Exomes 𝑓: 0.064 (3324 hom.)
• Consequence: RTEL1 NM_001283009.2 splice_region, intron
• Scores: Splicing: ADA: 0.0001018
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.05
• Publications: 5 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=-0.8).
• BP6: Variant 20-63687931-G-A is Benign according to our data. Variant chr20-63687931-G-A is described in ClinVar as Benign. ClinVar VariationId is 473905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0715 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	NM_001283009.2	MANE Select	c.1482-6G>A		splice_region intron	N/A	NP_001269938.1
	RTEL1	NM_032957.5		c.1554-6G>A		splice_region intron	N/A	NP_116575.3
	RTEL1	NM_016434.4		c.1482-6G>A		splice_region intron	N/A	NP_057518.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.1482-6G>A		splice_region intron	N/A	ENSP00000353332.5
	RTEL1	ENST00000508582.7	TSL:2	c.1554-6G>A		splice_region intron	N/A	ENSP00000424307.2
	RTEL1	ENST00000370018.7	TSL:1	c.1482-6G>A		splice_region intron	N/A	ENSP00000359035.3

Frequencies

GnomAD3 genomes AF: 0.0464 AC: 7057 AN: 152148 Hom.: 244 Cov.: 33

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0407

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0445

Gnomad FIN AF: 0.0440

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0732

Gnomad OTH AF: 0.0430

GnomAD2 exomes AF: 0.0474 AC: 11804 AN: 248810 AF XY: 0.0486

Gnomad AFR exome AF: 0.0111

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.0206

Gnomad EAS exome AF: 0.000708

Gnomad FIN exome AF: 0.0472

Gnomad NFE exome AF: 0.0676

Gnomad OTH exome AF: 0.0539

GnomAD4 exome AF: 0.0641 AC: 93508 AN: 1459800 Hom.: 3324 Cov.: 33 AF XY: 0.0637 AC XY: 46281 AN XY: 726186

African (AFR) AF: 0.0105 AC: 352 AN: 33464

American (AMR) AF: 0.0287 AC: 1285 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0209 AC: 547 AN: 26132

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39688

South Asian (SAS) AF: 0.0494 AC: 4258 AN: 86238

European-Finnish (FIN) AF: 0.0514 AC: 2675 AN: 52058

Middle Eastern (MID) AF: 0.0102 AC: 59 AN: 5760

European-Non Finnish (NFE) AF: 0.0729 AC: 81064 AN: 1111406

Other (OTH) AF: 0.0538 AC: 3248 AN: 60350

GnomAD4 genome AF: 0.0463 AC: 7050 AN: 152266 Hom.: 244 Cov.: 33 AF XY: 0.0454 AC XY: 3384 AN XY: 74458

African (AFR) AF: 0.0127 AC: 529 AN: 41544

American (AMR) AF: 0.0406 AC: 621 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 72 AN: 3470

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5178

South Asian (SAS) AF: 0.0439 AC: 212 AN: 4824

European-Finnish (FIN) AF: 0.0440 AC: 467 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0732 AC: 4976 AN: 68000

Other (OTH) AF: 0.0421 AC: 89 AN: 2114

Alfa AF: 0.0574 Hom.: 208

Bravo AF: 0.0421

Asia WGS AF: 0.0290 AC: 99 AN: 3478

EpiCase AF: 0.0682

EpiControl AF: 0.0629

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 01, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.1554-6G>A in intron 17 of RTEL1: This variant is not expected to have clinical significance because it has been identified in 7% (8722/125530) of European chr omosomes by the Genome Aggregation Databse (gnomAD, http://exac.broadinstitute.o rg; dbSNP rs76364377). ACMG/AMP Criteria applied: BA1; BP4.

not provided Benign:3

Aug 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 02, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dyskeratosis congenita Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.1
DANN	Benign	0.50
PhyloP100		-1.0
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.048
SpliceAI score (max)		0.080		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: rs76364377; hg19: chr20-62319284; COSMIC: COSV58898780; COSMIC: COSV58898780;