chr20-63659407-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

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

Scores

8
9
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.93
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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/exons MANE UniProt
RTEL1NM_001283009.2 linkuse as main transcriptc.5C>A p.Pro2His missense_variant 2/35 ENST00000360203.11
RTEL1-TNFRSF6BNR_037882.1 linkuse as main transcriptn.832C>A non_coding_transcript_exon_variant 2/38

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RTEL1ENST00000360203.11 linkuse as main transcriptc.5C>A p.Pro2His missense_variant 2/355 NM_001283009.2 A2Q9NZ71-6

Frequencies

GnomAD3 genomes
Cov.:
33
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
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024RTEL1: 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;.;.
MutationTaster
Benign
1.0
D;D;D;D
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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs757516930; hg19: chr20-62290760; API