rs200288187
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_198253.3(TERT):c.3257G>A(p.Arg1086His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,613,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. R1086C) has been classified as Uncertain significance.
Frequency
Consequence
NM_198253.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TERT | NM_198253.3 | c.3257G>A | p.Arg1086His | missense_variant | 15/16 | ENST00000310581.10 | |
TERT | NM_001193376.3 | c.3068G>A | p.Arg1023His | missense_variant | 14/15 | ||
TERT | NR_149162.3 | n.2965G>A | non_coding_transcript_exon_variant | 12/13 | |||
TERT | NR_149163.3 | n.2929G>A | non_coding_transcript_exon_variant | 12/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TERT | ENST00000310581.10 | c.3257G>A | p.Arg1086His | missense_variant | 15/16 | 1 | NM_198253.3 | P2 | |
ENST00000666708.1 | n.289-268C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000197 AC: 30AN: 152178Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000137 AC: 34AN: 249006Hom.: 0 AF XY: 0.000148 AC XY: 20AN XY: 135362
GnomAD4 exome AF: 0.000106 AC: 155AN: 1460924Hom.: 0 Cov.: 32 AF XY: 0.000113 AC XY: 82AN XY: 726804
GnomAD4 genome ? AF: 0.000197 AC: 30AN: 152296Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74452
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 11, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 07, 2022 | Variant summary: TERT c.3257G>A (p.Arg1086His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 249006 control chromosomes (gnomAD). The variant, c.3257G>A, has been reported in the literature in heterozygous state in individuals affected with phenotypes belonging to the TERT-related disease spectrum, i.e. thrombocytopenia, and dyskeratosis congenita (e.g. Gutierrez-Rodrigues_2019, Tometten_2021), but was also found in unaffected relatives (Gutierrez-Rodrigues_2019). These reports do not provide unequivocal conclusions about association of the variant with TERT-Related Disorders. A publication reported experimental evidence evaluating an impact on protein function, and found that the variant protein retained its telomere elongation capacity (Reilly_2021). Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 09, 2022 | BS3, BP4, PP2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34565437, 34019641, 30523342) - |
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1086 of the TERT protein (p.Arg1086His). This variant is present in population databases (rs200288187, gnomAD 0.08%). This missense change has been observed in individual(s) with clinical features of TERT-related conditions (PMID: 30523342, 34019641, 34565437). ClinVar contains an entry for this variant (Variation ID: 242237). 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 histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 10, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at