rs774657340
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_198253.3(TERT):c.863C>T(p.Ala288Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000201 in 1,594,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A288G) 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.863C>T | p.Ala288Val | missense_variant | 2/16 | ENST00000310581.10 | |
TERT | NM_001193376.3 | c.863C>T | p.Ala288Val | missense_variant | 2/15 | ||
TERT | NR_149162.3 | n.942C>T | non_coding_transcript_exon_variant | 2/13 | |||
TERT | NR_149163.3 | n.942C>T | non_coding_transcript_exon_variant | 2/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TERT | ENST00000310581.10 | c.863C>T | p.Ala288Val | missense_variant | 2/16 | 1 | NM_198253.3 | P2 | |
TERT | ENST00000334602.10 | c.863C>T | p.Ala288Val | missense_variant | 2/15 | 1 | A2 | ||
TERT | ENST00000460137.6 | c.863C>T | p.Ala288Val | missense_variant, NMD_transcript_variant | 2/13 | 1 | |||
TERT | ENST00000656021.1 | c.863C>T | p.Ala288Val | missense_variant, NMD_transcript_variant | 2/17 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152216Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000511 AC: 11AN: 215472Hom.: 0 AF XY: 0.0000340 AC XY: 4AN XY: 117590
GnomAD4 exome AF: 0.0000187 AC: 27AN: 1442334Hom.: 0 Cov.: 35 AF XY: 0.0000181 AC XY: 13AN XY: 716464
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152334Hom.: 0 Cov.: 34 AF XY: 0.0000268 AC XY: 2AN XY: 74490
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 12, 2023 | BP4, PP2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 12, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 35456430) - |
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 | Nov 19, 2021 | - - |
Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 01, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Dyskeratosis congenita Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 15, 2022 | The p.A288V variant (also known as c.863C>T), located in coding exon 2 of the TERT gene, results from a C to T substitution at nucleotide position 863. The alanine at codon 288 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
TERT-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 13, 2023 | The TERT c.863C>T variant is predicted to result in the amino acid substitution p.Ala288Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.027% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-1294138-G-A). It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/539214). 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
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at