chr5-1294764-G-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_198253.3(TERT):c.219+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000631 in 1,544,544 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_198253.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TERT | NM_198253.3 | c.219+7C>T | splice_region_variant, intron_variant | ENST00000310581.10 | |||
TERT | NM_001193376.3 | c.219+7C>T | splice_region_variant, intron_variant | ||||
TERT | NR_149162.3 | n.298+7C>T | splice_region_variant, intron_variant, non_coding_transcript_variant | ||||
TERT | NR_149163.3 | n.298+7C>T | splice_region_variant, intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TERT | ENST00000310581.10 | c.219+7C>T | splice_region_variant, intron_variant | 1 | NM_198253.3 | P2 | |||
TERT | ENST00000334602.10 | c.219+7C>T | splice_region_variant, intron_variant | 1 | A2 | ||||
TERT | ENST00000460137.6 | c.219+7C>T | splice_region_variant, intron_variant, NMD_transcript_variant | 1 | |||||
TERT | ENST00000656021.1 | c.219+7C>T | splice_region_variant, intron_variant, NMD_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.000348 AC: 53AN: 152188Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.000325 AC: 46AN: 141468Hom.: 0 AF XY: 0.000318 AC XY: 25AN XY: 78526
GnomAD4 exome AF: 0.000662 AC: 921AN: 1392248Hom.: 1 Cov.: 35 AF XY: 0.000613 AC XY: 422AN XY: 688432
GnomAD4 genome AF: 0.000348 AC: 53AN: 152296Hom.: 0 Cov.: 34 AF XY: 0.000295 AC XY: 22AN XY: 74464
ClinVar
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 26, 2017 | c.219+7C>T in Intron 1 of TERT: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.07% (46/70754) o f European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad .broadinstitute.org; dbSNP rs573817924). ACMG/AMP Criteria applied: BP4, BP7 (Ri chards 2015). - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
not provided Benign:2
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Dyskeratosis congenita Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 15, 2014 | The c.219+7C>T intronic variant results from a C to T substitution 7 nucleotides after coding exon 1 in the TERT gene. This variant was first identified in a 13 year old female who was diagnosed with Diamond Blackfan anemia at 6 months of age and was transfusion dependent and had telomere lengths below the first percentile; this variant was also identified in her reportedly healthy father, who had telomere lengths near the first percentile. In addition, both carried a promoter variant, c.-171A>T, in the DKC1 gene; however, authors felt neither variant explained the clinical picture of the affected daughter (Pavesi E et al. Pediatr Blood Cancer. 2009;53(3):411-6). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 3491 samples (6982 alleles) with coverage at this position. This nucleotide position is not well conserved in available vertebrate species on limited alignment. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this donor splice site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
Aplastic anemia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Dyskeratosis congenita, autosomal dominant 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
TERT-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 18, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at