chr5-1278750-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_198253.3(TERT):c.2177C>T(p.Thr726Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,614,044 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_198253.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TERT | NM_198253.3 | c.2177C>T | p.Thr726Met | missense_variant | Exon 6 of 16 | ENST00000310581.10 | NP_937983.2 | |
TERT | NM_001193376.3 | c.2177C>T | p.Thr726Met | missense_variant | Exon 6 of 15 | NP_001180305.1 | ||
TERT | NR_149162.3 | n.2256C>T | non_coding_transcript_exon_variant | Exon 6 of 13 | ||||
TERT | NR_149163.3 | n.2220C>T | non_coding_transcript_exon_variant | Exon 6 of 13 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152236Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251478Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135916
GnomAD4 exome AF: 0.0000937 AC: 137AN: 1461808Hom.: 0 Cov.: 32 AF XY: 0.0000880 AC XY: 64AN XY: 727206
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152236Hom.: 0 Cov.: 34 AF XY: 0.0000672 AC XY: 5AN XY: 74368
ClinVar
Submissions by phenotype
not provided Uncertain:2
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In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32487952, 32150348, 25562321, 23426163, 23901009, 26329388, 28813500, 26887940, 16990594, 21176016, 21323862, 17825470, 22775985, 35927969, 23716176, 16627250, 23538340, 36649908, 35106810) -
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 Uncertain:1
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not specified Uncertain:1
DNA sequence analysis of the TERT gene demonstrated a sequence change, c.2177C>T, in exon 6 that results in an amino acid change, p.Thr726Met. This sequence change has been described in the gnomAD database with a frequency of 0.01% in the European sub-population (dbSNP rs149566858). The p.Thr726Met change has been reported in individuals with aplastic anemia, dyskeratosis congenita, Hoyeraal Hreidarsson syndrome, and emphysema (PMID: 16627250, 25562321, 23538340, 26329388). This sequence change has also been identified in the unaffected parent of an individual with aplastic anemia (PMID: 16627250). The p.Thr726Met change affects a poorly conserved amino acid residue located in a domain of the TERT protein that is known to be functional. The p.Thr726Met substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Some studies have demonstrated that the p.Thr726Met change does not significantly impact telomerase enzyme activity (PMID: 26887940, 23901009, 16990594), while others have reported impaired enzyme activity in presence of this variant (PMID: 25562321, 28813500). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr726Met change remains unknown at this time. -
Interstitial lung disease 2 Uncertain:1
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Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
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Dyskeratosis congenita Uncertain:1
The p.T726M variant (also known as c.2177C>T), located in coding exon 6 of the TERT gene, results from a C to T substitution at nucleotide position 2177. The threonine at codon 726 is replaced by methionine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with TERT-related disorder (Liang J et al. Haematologica, 2006 May;91:656-8; Yamaguchi H et al. Int J Hematol, 2015 Nov;102:544-52; Stanley SE et al. J Clin Invest, 2015 Feb;125:563-70; Gurnari C et al. Hematol Oncol, 2022 Oct;40:812-817; Janczar S et al. Pediatr Blood Cancer, 2022 Oct;69:e29909). The majority of functional studies suggest this variant does not have a significant impact on telomerase activity; however, the physiological relevance of this finding is unclear (Xin ZT et al. Blood, 2007 Jan;109:524-32; Zaug AJ et al. Nucleic Acids Res, 2013 Oct;41:8969-78; Stanley SE et al. J Clin Invest, 2015 Feb;125:563-70; Chu TW et al. J Biol Chem, 2016 Apr;291:8374-86; Donaires FS et al. PLoS One, 2017 Aug;12:e0183287). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
TERT-related disorder Uncertain:1
The TERT c.2177C>T variant is predicted to result in the amino acid substitution p.Thr726Met. This variant has been reported in an individual with aplastic anemia, an individual with cirrhosis, alcoholism, and advanced hepatocellular carcinoma, an individual with emphysema who was a smoker, and an individual with dyskeratosis congenita (Liang et al. 2006. PubMed ID: 16627250; Table 2, Donaires. 2017. PubMed ID: 28813500; Table 3, Stanley. 2015. PubMed ID: 25562321; Table 2, Yamaguchi. 2015. PubMed ID: 26329388). Experimental studies provide conflicting evidence regarding the impact of this variant on telomerase activity (Figure 2, Donaires. 2017. PubMed ID: 28813500; Table 1, Gramatges et al. 2013. PubMed ID: 23538340; Stanley. 2015. PubMed ID: 25562321; Table 1, Zaug. 2013. PubMed ID: 23901009). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/39111/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Benign:1
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Dyskeratosis congenita, autosomal dominant 1 Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at