rs753991999

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7

The NM_198253.3(TERT):​c.1560G>A​(p.Leu520Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TERT
NM_198253.3 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.434

Publications

0 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: Benign. The variant received -11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.71).
BP6
Variant 5-1293326-C-T is Benign according to our data. Variant chr5-1293326-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 539284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.434 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TERTNM_198253.3 linkc.1560G>A p.Leu520Leu synonymous_variant Exon 2 of 16 ENST00000310581.10 NP_937983.2 O14746-1
TERTNM_001193376.3 linkc.1560G>A p.Leu520Leu synonymous_variant Exon 2 of 15 NP_001180305.1 O14746-3
TERTNR_149162.3 linkn.1639G>A non_coding_transcript_exon_variant Exon 2 of 13
TERTNR_149163.3 linkn.1639G>A non_coding_transcript_exon_variant Exon 2 of 13

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TERTENST00000310581.10 linkc.1560G>A p.Leu520Leu synonymous_variant Exon 2 of 16 1 NM_198253.3 ENSP00000309572.5 O14746-1
TERTENST00000334602.10 linkc.1560G>A p.Leu520Leu synonymous_variant Exon 2 of 15 1 ENSP00000334346.6 O14746-3
TERTENST00000460137.6 linkn.1560G>A non_coding_transcript_exon_variant Exon 2 of 13 1 ENSP00000425003.1 O14746-4
TERTENST00000656021.1 linkn.1560G>A non_coding_transcript_exon_variant Exon 2 of 17 ENSP00000499759.1 A0A590UK92

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152260
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000120
AC:
3
AN:
249556
AF XY:
0.00000738
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000868
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
AF:
0.00000274
AC:
4
AN:
1460700
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726674
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.0000894
AC:
4
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86248
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52296
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111976
Other (OTH)
AF:
0.00
AC:
0
AN:
60380
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.488
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152260
Hom.:
0
Cov.:
34
AF XY:
0.0000134
AC XY:
1
AN XY:
74390
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41468
American (AMR)
AF:
0.0000654
AC:
1
AN:
15294
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10632
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68038
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Benign:1
Apr 07, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dyskeratosis congenita Benign:1
Apr 04, 2020
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.71
CADD
Benign
3.8
DANN
Benign
0.46
PhyloP100
0.43
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=74/26
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs753991999; hg19: chr5-1293441; API