NM_198253.3:c.1573+445G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_198253.3(TERT):​c.1573+445G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 152,032 control chromosomes in the GnomAD database, including 18,486 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.49 ( 18486 hom., cov: 33)

Consequence

TERT
NM_198253.3 intron

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.915

Publications

26 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

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TERTNM_198253.3 linkc.1573+445G>T intron_variant Intron 2 of 15 ENST00000310581.10 NP_937983.2 O14746-1
TERTNM_001193376.3 linkc.1573+445G>T intron_variant Intron 2 of 14 NP_001180305.1 O14746-3
TERTNR_149162.3 linkn.1652+445G>T intron_variant Intron 2 of 12
TERTNR_149163.3 linkn.1652+445G>T intron_variant Intron 2 of 12

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TERTENST00000310581.10 linkc.1573+445G>T intron_variant Intron 2 of 15 1 NM_198253.3 ENSP00000309572.5 O14746-1
TERTENST00000334602.10 linkc.1573+445G>T intron_variant Intron 2 of 14 1 ENSP00000334346.6 O14746-3
TERTENST00000460137.6 linkn.1573+445G>T intron_variant Intron 2 of 12 1 ENSP00000425003.1 O14746-4
TERTENST00000656021.1 linkn.*197+96G>T intron_variant Intron 2 of 16 ENSP00000499759.1 A0A590UK92

Frequencies

GnomAD3 genomes
AF:
0.491
AC:
74571
AN:
151914
Hom.:
18470
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.473
Gnomad AMI
AF:
0.478
Gnomad AMR
AF:
0.584
Gnomad ASJ
AF:
0.371
Gnomad EAS
AF:
0.526
Gnomad SAS
AF:
0.350
Gnomad FIN
AF:
0.530
Gnomad MID
AF:
0.296
Gnomad NFE
AF:
0.490
Gnomad OTH
AF:
0.460
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
AF:
0.491
AC:
74628
AN:
152032
Hom.:
18486
Cov.:
33
AF XY:
0.493
AC XY:
36619
AN XY:
74308
show subpopulations
African (AFR)
AF:
0.473
AC:
19617
AN:
41466
American (AMR)
AF:
0.585
AC:
8939
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.371
AC:
1288
AN:
3470
East Asian (EAS)
AF:
0.527
AC:
2718
AN:
5160
South Asian (SAS)
AF:
0.350
AC:
1692
AN:
4828
European-Finnish (FIN)
AF:
0.530
AC:
5599
AN:
10556
Middle Eastern (MID)
AF:
0.305
AC:
89
AN:
292
European-Non Finnish (NFE)
AF:
0.490
AC:
33292
AN:
67954
Other (OTH)
AF:
0.455
AC:
959
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
1993
3986
5980
7973
9966
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
674
1348
2022
2696
3370
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.484
Hom.:
60334
Bravo
AF:
0.498
Asia WGS
AF:
0.434
AC:
1509
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
0.32
DANN
Benign
0.68
PhyloP100
-0.92
Mutation Taster
=100/0
polymorphism (auto)

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: rs2853672; hg19: chr5-1292983; API