rs199422295

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_198253.3(TERT):​c.2045G>A​(p.Gly682Asp) 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. G682R) 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

Scores

10
7
2

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 1.69

Publications

7 publications found
Variant links:
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, 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • dyskeratosis congenita, autosomal dominant 2
    Inheritance: 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 leukemia
    Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • dyskeratosis congenita
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Hoyeraal-Hreidarsson syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • melanoma, cutaneous malignant, susceptibility to, 9
    Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 21 uncertain in NM_198253.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TERTNM_198253.3 linkc.2045G>A p.Gly682Asp missense_variant Exon 5 of 16 ENST00000310581.10 NP_937983.2 O14746-1
TERTNM_001193376.3 linkc.2045G>A p.Gly682Asp missense_variant Exon 5 of 15 NP_001180305.1 O14746-3
TERTNR_149162.3 linkn.2124G>A non_coding_transcript_exon_variant Exon 5 of 13
TERTNR_149163.3 linkn.2124G>A non_coding_transcript_exon_variant Exon 5 of 13

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TERTENST00000310581.10 linkc.2045G>A p.Gly682Asp missense_variant Exon 5 of 16 1 NM_198253.3 ENSP00000309572.5 O14746-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
167544
AF XY:
0.00
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1413070
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
698768
African (AFR)
AF:
0.00
AC:
0
AN:
32214
American (AMR)
AF:
0.00
AC:
0
AN:
37742
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25316
East Asian (EAS)
AF:
0.00
AC:
0
AN:
36926
South Asian (SAS)
AF:
0.00
AC:
0
AN:
80242
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
48784
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4344
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1089012
Other (OTH)
AF:
0.00
AC:
0
AN:
58490
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.000106
Hom.:
0

ClinVar

Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link

Submissions by phenotype

Dyskeratosis congenita, autosomal dominant 1 Other:1
-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.49
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D;.
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Benign
0.52
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.6
M;M
PhyloP100
1.7
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-4.9
D;D
REVEL
Pathogenic
0.81
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0080
D;D
Polyphen
1.0
D;D
Vest4
0.73
MutPred
0.83
Loss of MoRF binding (P = 0.0549);Loss of MoRF binding (P = 0.0549);
MVP
0.99
MPC
2.5
ClinPred
0.99
D
GERP RS
4.7
Varity_R
0.83
gMVP
1.0
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs199422295; hg19: chr5-1279491; API