rs199422297
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_198253.3(TERT):c.2110C>T(p.Pro704Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000884 in 1,584,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P704P) has been classified as Likely benign.
Frequency
Consequence
NM_198253.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TERT | NM_198253.3 | c.2110C>T | p.Pro704Ser | missense_variant | 5/16 | ENST00000310581.10 | |
TERT | NM_001193376.3 | c.2110C>T | p.Pro704Ser | missense_variant | 5/15 | ||
TERT | NR_149162.3 | n.2189C>T | non_coding_transcript_exon_variant | 5/13 | |||
TERT | NR_149163.3 | n.2189C>T | non_coding_transcript_exon_variant | 5/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TERT | ENST00000310581.10 | c.2110C>T | p.Pro704Ser | missense_variant | 5/16 | 1 | NM_198253.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152182Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00000507 AC: 1AN: 197100Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 107652
GnomAD4 exome AF: 0.00000489 AC: 7AN: 1431824Hom.: 0 Cov.: 33 AF XY: 0.00000423 AC XY: 3AN XY: 709724
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152182Hom.: 0 Cov.: 34 AF XY: 0.0000404 AC XY: 3AN XY: 74322
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 14, 2022 | The c.2110C>T sequence change in exon 5 results in an amino acid change, p.Pro704Ser. The p.Pro704Ser change affects a poorly conserved amino acid residue located in a domain of the TERT protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro704Ser substitution. This sequence change has been reported in the homozygous state in two individuals with dyskeratosis congenital (PMID: 18042801, 18931339). It has also been described in the heterozygous state in three individuals from one family with pulmonary fibrosis and one individual with aplastic anemia (PMID: 1863588, 18931339). Multiple studies have found that the p.Pro704Ser change results in reduced telomerase activity (PMID: 18042801, 23901009. 18931339). This sequence change has been described in the gnomAD database in 2 individuals which corresponds to a population frequency of 0.0009% (dbSNP rs199422297). Based on these evidences this sequence change is classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 22, 2022 | Observed in individuals with TERT-related disorders in published literature (Du 2009, Batista 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30523342, 23901009, 18042801, 18635888, 23538340, 18931339, 27418648, 21602826, 28099038) - |
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 704 of the TERT protein (p.Pro704Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of TERT-related conditions (PMID: 18042801, 18635888, 18931339, 21602826, 27418648, 30523342; Invitae). ClinVar contains an entry for this variant (Variation ID: 39108). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects TERT function (PMID: 18042801, 21602826, 23901009, 25365545). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Hereditary cancer-predisposing syndrome;C0265965:Dyskeratosis congenita Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 16, 2021 | The p.P704S pathogenic mutation (also known as c.2110C>T), located in coding exon 5 of the TERT gene, results from a C to T substitution at nucleotide position 2110. The proline at codon 704 is replaced by serine, an amino acid with similar properties. This mutation has demonstrated both an autosomal recessive inheritance presenting with a more severe phenotype as well as autosomal dominant inheritance with variable presentation, age of onset, and reduced penetrance. This alteration was first reported in homozygous state in a proband diagnosed with dyskeratosis congenita and additional abnormalities; one parent who was compound heterozygous with another alteration had shortened telomeres, while the other heterozygous parent was asymptomatic in the 6th decade of life. Functional analysis in this study demonstrated that this mutation severely reduced telomerase activity to 13% of wild type (Du HY et al. Blood, 2008 Feb;111:1128-30). This mutation was also identified in the heterozygous state in three siblings with pulmonary fibrosis, and other unrelated individuals with myelodysplastic syndrome and/or pulmonary fibrosis (Cronkhite JT et al. Am. J. Respir. Crit. Care Med., 2008 Oct;178:729-37; Keel SB et al. Haematologica, 2016 11;101:1343-1350; Gutierrez-Rodrigues F et al. Genet Med, 2019 07;21:1594-1602). Additional in vitro functional studies demonstrated that this mutation significantly reduces activity and processivity of telomerase (Batista LF et al. Nature, 2011 Jun;474:399-402; Zaug AJ et al. Nucleic Acids Res., 2013 Oct;41:8969-78). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Dyskeratosis congenita, autosomal dominant 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 27, 2023 | - - |
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 - |
Autosomal recessive dyskeratosis congenita 4 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2008 | - - |
Dyskeratosis congenita, autosomal dominant 1 Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at