20-63694428-G-C

Position:

• chr20-63694428-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001283009.2(RTEL1):​c.3049G>C​(p.Asp1017His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1017N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.996

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.3049G>C	p.Asp1017His	missense_variant	31/35	ENST00000360203.11	NP_001269938.1
RTEL1-TNFRSF6B	NR_037882.1	n.3876G>C		non_coding_transcript_exon_variant	31/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11	c.3049G>C	p.Asp1017His	missense_variant	31/35	5	NM_001283009.2	ENSP00000353332	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246952 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134440

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460072 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726274

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain: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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 1017 of the RTEL1 protein (p.Asp1017His). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RTEL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1410857). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.;.;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.023
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.1	M;.;M;.
MutationTaster	Benign	0.94	N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.1	N;N;N;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0060	D;D;D;.
Sift4G	Uncertain	0.034	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.48
MutPred		0.26		Gain of helix (P = 0.0425);.;Gain of helix (P = 0.0425);.;
MVP		0.94
ClinPred		0.43	T
GERP RS		2.8
Varity_R		0.12
gMVP		0.38

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: rs61736617; hg19: chr20-62325781;