20-63694486-C-T

Variant names:

• chr20-63694486-C-T
• rs138576158
• NM_001283009.2:c.3107C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001283009.2(RTEL1):​c.3107C>T​(p.Thr1036Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RTEL1 NM_001283009.2 missense, splice_region
• Scores: Splicing: ADA: 0.2440
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00900

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13899404).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.3107C>T	p.Thr1036Ile	missense_variant, splice_region_variant	Exon 31 of 35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11	c.3107C>T	p.Thr1036Ile	missense_variant, splice_region_variant	Exon 31 of 35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7	c.3179C>T	p.Thr1060Ile	missense_variant, splice_region_variant	Exon 31 of 35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7	c.3107C>T	p.Thr1036Ile	missense_variant, splice_region_variant	Exon 31 of 35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6	n.*709C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 28 of 35	5		ENSP00000457428.1
RTEL1-TNFRSF6B	ENST00000492259.6	n.*709C>T		3_prime_UTR_variant	Exon 28 of 35	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000411 AC: 1 AN: 243572 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132666

Gnomad AFR exome AF: 0.0000626

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T1036I variant (also known as c.3107C>T), located in coding exon 30 of the RTEL1 gene, results from a C to T substitution at nucleotide position 3107. The threonine at codon 1036 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.15	T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.67	T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.1	L;.;L;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.2	N;N;N;.
REVEL	Uncertain	0.31
Sift	Benign	0.15	T;T;T;.
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.078	B;B;B;.
Vest4		0.19
MutPred		0.15		Loss of glycosylation at T1036 (P = 0.0016);.;Loss of glycosylation at T1036 (P = 0.0016);.;
MVP		0.67
ClinPred		0.031	T
GERP RS		-1.4
Varity_R		0.044
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.24
dbscSNV1_RF	Benign	0.45
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: 39

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138576158; hg19: chr20-62325839;