rs199422296
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_198253.3(TERT):c.2029G>T(p.Gly677Cys) 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 not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G677D) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TERT
NM_198253.3 missense
NM_198253.3 missense
Scores
12
6
Clinical Significance
Conservation
PhyloP100: 1.72
Publications
2 publications found
Genes affected
TERT (HGNC:11730): (telomerase reverse transcriptase) Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with reverse transcriptase activity, encoded by this gene, and an RNA component which serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells resulting in progressive shortening of telomeres. Deregulation of telomerase expression in somatic cells may be involved in oncogenesis. Studies in mouse suggest that telomerase also participates in chromosomal repair, since de novo synthesis of telomere repeats may occur at double-stranded breaks. Alternatively spliced variants encoding different isoforms of telomerase reverse transcriptase have been identified; the full-length sequence of some variants has not been determined. Alternative splicing at this locus is thought to be one mechanism of regulation of telomerase activity. [provided by RefSeq, Jul 2008]
TERT Gene-Disease associations (from GenCC):
- pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
- dyskeratosis congenita, autosomal dominant 2Inheritance: Unknown, SD, AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen, Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
- acute myeloid leukemiaInheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 8 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 25 uncertain in NM_198253.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.97
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_198253.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TERT | TSL:1 MANE Select | c.2029G>T | p.Gly677Cys | missense | Exon 5 of 16 | ENSP00000309572.5 | O14746-1 | ||
| TERT | TSL:1 | c.2029G>T | p.Gly677Cys | missense | Exon 5 of 15 | ENSP00000334346.6 | O14746-3 | ||
| TERT | TSL:1 | n.2029G>T | non_coding_transcript_exon | Exon 5 of 13 | ENSP00000425003.1 | O14746-4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1405768Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 694494
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1405768
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
694494
African (AFR)
AF:
AC:
0
AN:
31902
American (AMR)
AF:
AC:
0
AN:
36702
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25254
East Asian (EAS)
AF:
AC:
0
AN:
36418
South Asian (SAS)
AF:
AC:
0
AN:
79762
European-Finnish (FIN)
AF:
AC:
0
AN:
48346
Middle Eastern (MID)
AF:
AC:
0
AN:
4334
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1084832
Other (OTH)
AF:
AC:
0
AN:
58218
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
ClinVar submissions
View on ClinVar Significance:not provided
Revision:no classification provided
Pathogenic
VUS
Benign
Condition
-
-
-
Dyskeratosis congenita, autosomal dominant 1 (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of catalytic residue at P673 (P = 0.0775)
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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