20-63688038-C-T

Position:

• chr20-63688038-C-T

Variant summary

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

The NM_001283009.2(RTEL1):​c.1583C>T​(p.Ala528Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,344 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A528A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.41

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.1583C>T	p.Ala528Val	missense_variant	18/35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11	c.1583C>T	p.Ala528Val	missense_variant	18/35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7	c.1655C>T	p.Ala552Val	missense_variant	18/35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7	c.1583C>T	p.Ala528Val	missense_variant	18/35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6	n.1667C>T		non_coding_transcript_exon_variant	16/35	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249380 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135496

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460344 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726468

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

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

Aug 05, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 528 of the RTEL1 protein (p.Ala528Val). This variant is present in population databases (rs760398738, gnomAD 0.002%). 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: 1461593). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	Uncertain	0.38
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.8	L;.;L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.1	D;D;D;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.012	D;T;T;.
Sift4G	Benign	0.10	T;T;T;T
Polyphen		0.91	P;D;P;.
Vest4		0.40
MutPred		0.31		Loss of disorder (P = 0.046);.;Loss of disorder (P = 0.046);.;
MVP		0.47
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.41
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs760398738; hg19: chr20-62319391;