rs115303435

chr20-63694806-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001283009.2(RTEL1):c.3175G>A(p.Ala1059Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,612,396 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1059A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (32 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.324

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028603077).
• BP6: Variant 20-63694806-G-A is Benign according to our data. Variant chr20-63694806-G-A is described in ClinVar as [Benign]. Clinvar id is 473918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00157 (239/152352) while in subpopulation EAS AF= 0.0367 (190/5174). AF 95% confidence interval is 0.0325. There are 5 homozygotes in gnomad4. There are 133 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2	c.3175G>A	p.Ala1059Thr	missense_variant	32/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1	n.4002G>A		non_coding_transcript_exon_variant	32/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.3175G>A	p.Ala1059Thr	missense_variant	32/35	5	NM_001283009.2	A2

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152234 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0368

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00318 AC: 790 AN: 248088 Hom.: 12 AF XY: 0.00293 AC XY: 395 AN XY: 135034

Gnomad AFR exome AF: 0.000757

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0398

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00141 AC: 2062 AN: 1460044 Hom.: 32 Cov.: 35 AF XY: 0.00137 AC XY: 995 AN XY: 726326

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0444

Gnomad4 SAS exome AF: 0.000904

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000423

Gnomad4 OTH exome AF: 0.00260

GnomAD4 genome AF: 0.00157 AC: 239 AN: 152352 Hom.: 5 Cov.: 33 AF XY: 0.00179 AC XY: 133 AN XY: 74498

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0367

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000386 Hom.: 0

Bravo AF: 0.00172

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000461 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00301 AC: 361

Asia WGS AF: 0.0140 AC: 51 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 18, 2021

This variant is associated with the following publications: (PMID: 30462709) -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Dyskeratosis congenita Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	12
Dann	Uncertain	0.98
DEOGEN2	Benign	0.12	T;.;.;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.59	T;T;T;T
MetaRNN	Benign	0.0029	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.92	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.15	T;T;T;T
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.18	B;B;B;.
Vest4		0.091
MVP		0.42
ClinPred		0.00041	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.041
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs115303435; hg19: chr20-62326159; COSMIC: COSV99422698; COSMIC: COSV99422698;