chr20-63659407-C-A

Variant names:

• chr20-63659407-C-A
• rs757516930
• NM_001283009.2:c.5C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001283009.2(RTEL1):​c.5C>A​(p.Pro2His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P2P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.93
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.5C>A	p.Pro2His	missense_variant	Exon 2 of 35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11	c.5C>A	p.Pro2His	missense_variant	Exon 2 of 35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7	c.5C>A	p.Pro2His	missense_variant	Exon 2 of 35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7	c.5C>A	p.Pro2His	missense_variant	Exon 2 of 35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6	n.5C>A		non_coding_transcript_exon_variant	Exon 1 of 35	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251312 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RTEL1: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;.;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.63	T;T;T;T;T
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.6	M;M;M;.;.
PhyloP100		6.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.9	D;D;D;D;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;.
Polyphen		1.0	D;D;D;.;.
Vest4		0.57
MutPred		0.34		Loss of catalytic residue at P2 (P = 0.0016);Loss of catalytic residue at P2 (P = 0.0016);Loss of catalytic residue at P2 (P = 0.0016);Loss of catalytic residue at P2 (P = 0.0016);Loss of catalytic residue at P2 (P = 0.0016);
MVP		0.79
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.76
gMVP		0.82
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs757516930; hg19: chr20-62290760;