20-63692975-G-C

Variant names:

• chr20-63692975-G-C
• rs61736614
• NM_001283009.2:c.2823G>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.2823G>C​(p.Glu941Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00617 in 1,612,596 control chromosomes in the GnomAD database, including 515 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E941A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.031 (258 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (257 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.291
• 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 (MetaRNN=0.0016821921).
• BP6: Variant 20-63692975-G-C is Benign according to our data. Variant chr20-63692975-G-C is described in ClinVar as Benign. ClinVar VariationId is 473916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 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.2823G>C	p.Glu941Asp	missense	Exon 29 of 35	NP_001269938.1
	RTEL1	NM_032957.5		c.2895G>C	p.Glu965Asp	missense	Exon 29 of 35	NP_116575.3
	RTEL1	NM_016434.4		c.2823G>C	p.Glu941Asp	missense	Exon 29 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.2823G>C	p.Glu941Asp	missense	Exon 29 of 35	ENSP00000353332.5
	RTEL1	ENST00000508582.7	TSL:2	c.2895G>C	p.Glu965Asp	missense	Exon 29 of 35	ENSP00000424307.2
	RTEL1	ENST00000370018.7	TSL:1	c.2823G>C	p.Glu941Asp	missense	Exon 29 of 35	ENSP00000359035.3

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 4741 AN: 152192 Hom.: 257 Cov.: 33

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.00798 AC: 1990 AN: 249522 AF XY: 0.00552

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.00527

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000339

Gnomad OTH exome AF: 0.00460

GnomAD4 exome AF: 0.00356 AC: 5194 AN: 1460286 Hom.: 257 Cov.: 33 AF XY: 0.00306 AC XY: 2220 AN XY: 726446

African (AFR) AF: 0.117 AC: 3904 AN: 33480

American (AMR) AF: 0.00655 AC: 293 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52068

Middle Eastern (MID) AF: 0.00590 AC: 34 AN: 5766

European-Non Finnish (NFE) AF: 0.000416 AC: 463 AN: 1111818

Other (OTH) AF: 0.00774 AC: 467 AN: 60362

GnomAD4 genome AF: 0.0312 AC: 4757 AN: 152310 Hom.: 258 Cov.: 33 AF XY: 0.0300 AC XY: 2235 AN XY: 74484

African (AFR) AF: 0.108 AC: 4467 AN: 41538

American (AMR) AF: 0.0141 AC: 216 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68010

Other (OTH) AF: 0.0232 AC: 49 AN: 2116

Alfa AF: 0.00356 Hom.: 7

Bravo AF: 0.0361

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.102 AC: 448

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00976 AC: 1179

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000534

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 30, 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

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
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	10
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.032
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-0.29
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.075
Sift	Benign	0.091	T
Sift4G	Benign	0.13	T
Polyphen		0.61	P
Vest4		0.22
MutPred		0.33		Loss of ubiquitination at K944 (P = 0.0656)
MVP		0.35
ClinPred		0.027	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.37
Mutation Taster		=90/10	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: rs61736614; hg19: chr20-62324328;