chr5-1279409-C-G
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP3
The NM_198253.3(TERT):c.2012G>C(p.Arg671Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R671G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_198253.3 missense
Scores
Clinical Significance
Conservation
Publications
- pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
- dyskeratosis congenita, autosomal dominant 2Inheritance: AR, AD, SD, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
- acute myeloid leukemiaInheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- dyskeratosis congenitaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Hoyeraal-Hreidarsson syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- melanoma, cutaneous malignant, susceptibility to, 9Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Genome browser will be placed here
ACMG classification
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TERT | NM_198253.3 | c.2012G>C | p.Arg671Pro | missense_variant | Exon 5 of 16 | ENST00000310581.10 | NP_937983.2 | |
TERT | NM_001193376.3 | c.2012G>C | p.Arg671Pro | missense_variant | Exon 5 of 15 | NP_001180305.1 | ||
TERT | NR_149162.3 | n.2091G>C | non_coding_transcript_exon_variant | Exon 5 of 13 | ||||
TERT | NR_149163.3 | n.2091G>C | non_coding_transcript_exon_variant | Exon 5 of 13 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not specified Uncertain:1
DNA sequence analysis of the TERT gene demonstrated a sequence change, c.2012G>C, in exon 5 that results in an amino acid change, p.Arg671Pro. The p.Arg671Pro change affects a poorly conserved amino acid residue located in a domain of the TERT protein that is known to be functional. This sequence change is absent from the large population databases (ExAC and gnomAD). In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg671Pro substitution. This particular amino acid change does not appear to have been described in the literature in other patients with TERT related disorders, however, a different sequence change affecting the same amino acid residue (p.Arg671Trp) has been described in a patient with personal and family history of pulmonary fibrosis (PMID: 20502709). They also demonstrated reduction in in vitro telomerase activity for this variant measured by the telomere repeat amplification protocol (TRAP) assay. The p.Arg671Pro amino acid change also occurs in a region of the TERT gene where other missense sequence changes have been described in patients with TERT-related disorders. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg671Pro change remains unknown at this time. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at