rs199422272
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NR_001566.1(TERC):n.116C>T variant causes a non coding transcript exon change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
TERC
NR_001566.1 non_coding_transcript_exon
NR_001566.1 non_coding_transcript_exon
Scores
2
Clinical Significance
Conservation
PhyloP100: 3.90
Genes affected
TERC (HGNC:11727): (telomerase RNA component) Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with reverse transcriptase activity, and an RNA component, encoded by this gene, that serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells resulting in progressive shortening of telomeres. Deregulation of telomerase expression in somatic cells may be involved in oncogenesis. Studies in mouse suggest that telomerase also participates in chromosomal repair, since de novo synthesis of telomere repeats may occur at double-stranded breaks. Mutations in this gene cause autosomal dominant dyskeratosis congenita, and may also be associated with some cases of aplastic anemia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-169764945-G-A is Pathogenic according to our data. Variant chr3-169764945-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7326.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr3-169764945-G-A is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.14). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TERC | NR_001566.1 | n.116C>T | non_coding_transcript_exon_variant | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
Telomerase-vert | ENST00000363312.1 | n.103C>T | non_coding_transcript_exon_variant | 1/1 | |||||
TERC | ENST00000602385.1 | n.116C>T | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 0
GnomAD4 exome
Cov.:
0
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Dyskeratosis congenita, autosomal dominant 1 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | curation | GeneReviews | May 10, 2012 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 26, 2020 | This variant is located within the template/pseudoknot domain of the TERC RNA component, which is required for RNA or RNP stability (PMID: 15082312, 21844345). Functional studies testing the effect of this variant on TERC secondary structure or function have not been reported. This variant has been observed in individual(s) with aplastic anemia (PMID: 14630445). ClinVar contains an entry for this variant (Variation ID: 7326). This variant is not present in population databases (ExAC no frequency). This variant occurs in the TERC gene, which encodes an RNA molecule that does not result in a protein product. 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. - |
Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 15, 2003 | - - |
Pulmonary fibrosis Pathogenic:1
Likely risk allele, no assertion criteria provided | research | Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center | Jun 09, 2022 | Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 15, 2019 | DNA sequence analysis of the TERC gene demonstrated a sequence change, n.116C>T. This sequence change affects a highly conserved nucleotide located in a domain of the telomerase RNA that is known to be functional. This sequence change has not been described in population databases (gnomAD, ExAC). The n.116C>T change has been identified in individuals with aplastic anemia, telomeres shortening, and thrombocytopenia (PMID: 20022961, 14630445, 16670076). Functional studies revealed a partial loss of function in telomerase catalytic activation in the presence of this sequence change (PMID: 20022961). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at