rs190887884

chr20-63690937-G-Achr20-63690937-G-T

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.2546G>A(p.Gly849Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,550,632 control chromosomes in the GnomAD database, including 210 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G849G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (20 hom., cov: 33)
  • Exomes 𝑓: 0.014 (190 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.173

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=0.0025148392).
• BP6: Variant 20-63690937-G-A is Benign according to our data. Variant chr20-63690937-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 212073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63690937-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0107 (1637/152292) while in subpopulation NFE AF= 0.0156 (1058/67988). AF 95% confidence interval is 0.0148. There are 20 homozygotes in gnomad4. There are 824 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2	c.2546G>A	p.Gly849Asp	missense_variant	27/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1	n.3373G>A		non_coding_transcript_exon_variant	27/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.2546G>A	p.Gly849Asp	missense_variant	27/35	5	NM_001283009.2	A2

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1636 AN: 152174 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.00405

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0156

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.0102 AC: 1583 AN: 155810 Hom.: 16 AF XY: 0.0101 AC XY: 835 AN XY: 82750

Gnomad AFR exome AF: 0.00279

Gnomad AMR exome AF: 0.00460

Gnomad ASJ exome AF: 0.00704

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00624

Gnomad FIN exome AF: 0.0168

Gnomad NFE exome AF: 0.0160

Gnomad OTH exome AF: 0.00753

GnomAD4 exome AF: 0.0143 AC: 20019 AN: 1398340 Hom.: 190 Cov.: 34 AF XY: 0.0143 AC XY: 9835 AN XY: 690034

Gnomad4 AFR exome AF: 0.00211

Gnomad4 AMR exome AF: 0.00480

Gnomad4 ASJ exome AF: 0.00705

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00655

Gnomad4 FIN exome AF: 0.0173

Gnomad4 NFE exome AF: 0.0163

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.0107 AC: 1637 AN: 152292 Hom.: 20 Cov.: 33 AF XY: 0.0111 AC XY: 824 AN XY: 74468

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.0187

Gnomad4 NFE AF: 0.0156

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0136 Hom.: 19

Bravo AF: 0.00985

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.00216 AC: 9

ESP6500EA AF: 0.0136 AC: 113

ExAC AF: 0.00934 AC: 968

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 27, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 18, 2020

- -

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	0.10
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	9.9
Dann	Benign	0.79
DEOGEN2	Benign	0.22	T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.51	T;T;T;T
MetaRNN	Benign	0.0025	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.0	D;D;D;.
REVEL	Benign	0.011
Sift	Benign	0.20	T;T;T;.
Sift4G	Benign	0.071	T;T;T;T
Polyphen		0.0030	B;B;B;.
Vest4		0.26
ClinPred		0.0041	T
GERP RS		-0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.097
gMVP		0.19

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: rs190887884; hg19: chr20-62322290;