rs3848668

chr20-63661919-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001283009.2(RTEL1):c.371A>G(p.Asn124Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0731 in 1,613,524 control chromosomes in the GnomAD database, including 4,760 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N124D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.057 (343 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4417 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.70

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025758743).
• BP6: Variant 20-63661919-A-G is Benign according to our data. Variant chr20-63661919-A-G is described in ClinVar as [Benign]. Clinvar id is 1169883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63661919-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2	c.371A>G	p.Asn124Ser	missense_variant	4/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1	n.1198A>G		non_coding_transcript_exon_variant	4/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.371A>G	p.Asn124Ser	missense_variant	4/35	5	NM_001283009.2	A2

Frequencies

GnomAD3 genomes AF: 0.0575 AC: 8726 AN: 151878 Hom.: 344 Cov.: 32

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0609

Gnomad ASJ AF: 0.0464

Gnomad EAS AF: 0.000972

Gnomad SAS AF: 0.0469

Gnomad FIN AF: 0.0655

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0858

Gnomad OTH AF: 0.0565

GnomAD3 exomes AF: 0.0616 AC: 15490 AN: 251396 Hom.: 584 AF XY: 0.0624 AC XY: 8480 AN XY: 135896

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.0645

Gnomad ASJ exome AF: 0.0469

Gnomad EAS exome AF: 0.00152

Gnomad SAS exome AF: 0.0522

Gnomad FIN exome AF: 0.0648

Gnomad NFE exome AF: 0.0803

Gnomad OTH exome AF: 0.0673

GnomAD4 exome AF: 0.0748 AC: 109251 AN: 1461528 Hom.: 4417 Cov.: 32 AF XY: 0.0743 AC XY: 54030 AN XY: 727054

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.0619

Gnomad4 ASJ exome AF: 0.0469

Gnomad4 EAS exome AF: 0.000831

Gnomad4 SAS exome AF: 0.0523

Gnomad4 FIN exome AF: 0.0669

Gnomad4 NFE exome AF: 0.0832

Gnomad4 OTH exome AF: 0.0647

GnomAD4 genome AF: 0.0574 AC: 8719 AN: 151996 Hom.: 343 Cov.: 32 AF XY: 0.0568 AC XY: 4219 AN XY: 74274

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.0608

Gnomad4 ASJ AF: 0.0464

Gnomad4 EAS AF: 0.000975

Gnomad4 SAS AF: 0.0459

Gnomad4 FIN AF: 0.0655

Gnomad4 NFE AF: 0.0858

Gnomad4 OTH AF: 0.0564

Alfa AF: 0.0729 Hom.: 791

Bravo AF: 0.0538

TwinsUK AF: 0.0882 AC: 327

ALSPAC AF: 0.0789 AC: 304

ESP6500AA AF: 0.0175 AC: 77

ESP6500EA AF: 0.0828 AC: 712

ExAC AF: 0.0613 AC: 7439

Asia WGS AF: 0.0330 AC: 116 AN: 3478

EpiCase AF: 0.0844

EpiControl AF: 0.0784

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

Feb 06, 2019

- -

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.

Oct 25, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	5.4
Dann	Benign	0.61
DEOGEN2	Benign	0.18	T;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.85	T;T;T;D
MetaRNN	Benign	0.0026	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.24	N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.050	N;N;N;N
REVEL	Benign	0.068
Sift	Benign	0.79	T;T;T;T
Sift4G	Benign	0.75	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.019
ClinPred		0.0010	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs3848668; hg19: chr20-62293272; COSMIC: COSV58894154; COSMIC: COSV58894154;