rs199422306
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_198253.3(TERT):c.3329C>T(p.Thr1110Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000862 in 1,611,632 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1110A) has been classified as Likely benign.
Frequency
Consequence
NM_198253.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TERT | NM_198253.3 | c.3329C>T | p.Thr1110Met | missense_variant | 16/16 | ENST00000310581.10 | |
TERT | NM_001193376.3 | c.3140C>T | p.Thr1047Met | missense_variant | 15/15 | ||
TERT | NR_149162.3 | n.3037C>T | non_coding_transcript_exon_variant | 13/13 | |||
TERT | NR_149163.3 | n.3001C>T | non_coding_transcript_exon_variant | 13/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TERT | ENST00000310581.10 | c.3329C>T | p.Thr1110Met | missense_variant | 16/16 | 1 | NM_198253.3 | P2 | |
ENST00000666708.1 | n.289-876G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000330 AC: 8AN: 242766Hom.: 0 AF XY: 0.0000454 AC XY: 6AN XY: 132168
GnomAD4 exome AF: 0.0000918 AC: 134AN: 1459404Hom.: 0 Cov.: 31 AF XY: 0.0000896 AC XY: 65AN XY: 725848
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74352
ClinVar
Submissions by phenotype
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 - |
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 21, 2022 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1110 of the TERT protein (p.Thr1110Met). This variant is present in population databases (rs199422306, gnomAD 0.01%). This missense change has been observed in individual(s) with idiopathic pulmonary fibrosis and telomeropathies (PMID: 17392301, 30523342). ClinVar contains an entry for this variant (Variation ID: 39122). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects TERT function (PMID: 17392301). 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. - |
Aplastic anemia;C0023467:Acute myeloid leukemia;C3151443:Dyskeratosis congenita, autosomal dominant 2;C3553617:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1;C3554574:Melanoma, cutaneous malignant, susceptibility to, 9;C4551974:Dyskeratosis congenita, autosomal dominant 1;C5561926:Interstitial lung disease 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 04, 2021 | - - |
Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 25, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 19, 2023 | Observed in individuals with shortened telomeres and personal history of idiopathic pulmonary fibrosis or thrombocytopenia in published literature (Armanios et al., 2007; Gutierrez-Rodrigues et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23716176, 21520174, 20301779, 17392301, 28373299, 17825470, 23618685, 31426295, 30523342, 34019641) - |
Interstitial lung disease 2 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