rs144477693

chr20-63695520-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001283009.2(RTEL1):c.3692C>T(p.Thr1231Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,612,090 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 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. T1231T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0053 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (7 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -7.25

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030531585).
• BP6: Variant 20-63695520-C-T is Benign according to our data. Variant chr20-63695520-C-T is described in ClinVar as [Benign]. Clinvar id is 540956.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-63695520-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00534 (813/152308) while in subpopulation AFR AF= 0.0184 (765/41560). AF 95% confidence interval is 0.0173. There are 6 homozygotes in gnomad4. There are 391 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2	c.3692C>T	p.Thr1231Met	missense_variant	34/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1	n.4519C>T		non_coding_transcript_exon_variant	34/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.3692C>T	p.Thr1231Met	missense_variant	34/35	5	NM_001283009.2	A2

Frequencies

GnomAD3 genomes AF: 0.00532 AC: 809 AN: 152190 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00129 AC: 317 AN: 245850 Hom.: 2 AF XY: 0.000916 AC XY: 123 AN XY: 134232

Gnomad AFR exome AF: 0.0182

Gnomad AMR exome AF: 0.000725

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000455

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000554 AC: 808 AN: 1459782 Hom.: 7 Cov.: 34 AF XY: 0.000485 AC XY: 352 AN XY: 726186

Gnomad4 AFR exome AF: 0.0184

Gnomad4 AMR exome AF: 0.000873

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00534 AC: 813 AN: 152308 Hom.: 6 Cov.: 33 AF XY: 0.00525 AC XY: 391 AN XY: 74482

Gnomad4 AFR AF: 0.0184

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00250 Hom.: 1

Bravo AF: 0.00560

ESP6500AA AF: 0.0176 AC: 77

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00165 AC: 198

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	0.18
Dann	Benign	0.56
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N;N;N
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.087
Sift	Benign	0.23	T
Sift4G	Benign	0.34	T
Polyphen		0.0010	B
Vest4		0.11
MVP		0.22
ClinPred		0.0084	T
GERP RS		-5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs144477693; hg19: chr20-62326873;