5-1293918-G-A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_198253.3(TERT):​c.968C>T​(p.Pro323Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,542,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P323R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

3
16

Clinical Significance

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

Conservation

PhyloP100: -2.74

Publications

2 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 -12 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.036429316).
BP6
Variant 5-1293918-G-A is Benign according to our data. Variant chr5-1293918-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 846482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TERTNM_198253.3 linkc.968C>T p.Pro323Leu missense_variant Exon 2 of 16 ENST00000310581.10 NP_937983.2 O14746-1
TERTNM_001193376.3 linkc.968C>T p.Pro323Leu missense_variant Exon 2 of 15 NP_001180305.1 O14746-3
TERTNR_149162.3 linkn.1047C>T non_coding_transcript_exon_variant Exon 2 of 13
TERTNR_149163.3 linkn.1047C>T 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.968C>T p.Pro323Leu missense_variant Exon 2 of 16 1 NM_198253.3 ENSP00000309572.5 O14746-1
TERTENST00000334602.10 linkc.968C>T p.Pro323Leu missense_variant Exon 2 of 15 1 ENSP00000334346.6 O14746-3
TERTENST00000460137.6 linkn.968C>T non_coding_transcript_exon_variant Exon 2 of 13 1 ENSP00000425003.1 O14746-4
TERTENST00000656021.1 linkn.968C>T non_coding_transcript_exon_variant Exon 2 of 17 ENSP00000499759.1 A0A590UK92

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152170
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000392
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:
0.0000202
AC:
3
AN:
148816
AF XY:
0.0000253
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000809
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:
0.0000101
AC:
14
AN:
1389952
Hom.:
0
Cov.:
32
AF XY:
0.0000160
AC XY:
11
AN XY:
686060
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31616
American (AMR)
AF:
0.0000559
AC:
2
AN:
35752
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25180
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35742
South Asian (SAS)
AF:
0.0000126
AC:
1
AN:
79314
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
39454
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5698
European-Non Finnish (NFE)
AF:
0.0000102
AC:
11
AN:
1079210
Other (OTH)
AF:
0.00
AC:
0
AN:
57986
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
2
4
5
7
9
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:
0.0000394
AC:
6
AN:
152170
Hom.:
0
Cov.:
34
AF XY:
0.0000538
AC XY:
4
AN XY:
74322
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41426
American (AMR)
AF:
0.000392
AC:
6
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5176
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68030
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.417
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

Genome 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
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000302

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
Nov 23, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dyskeratosis congenita Benign:1
Dec 06, 2024
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
AlphaMissense
Benign
0.065
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
0.031
DANN
Benign
0.62
DEOGEN2
Uncertain
0.47
T;.
Eigen
Benign
-2.1
Eigen_PC
Benign
-2.2
FATHMM_MKL
Benign
0.018
N
LIST_S2
Benign
0.55
T;T
M_CAP
Uncertain
0.19
D
MetaRNN
Benign
0.036
T;T
MetaSVM
Uncertain
-0.13
T
MutationAssessor
Benign
0.46
N;N
PhyloP100
-2.7
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-1.6
N;N
REVEL
Benign
0.25
Sift
Benign
0.45
T;T
Sift4G
Benign
0.46
T;T
Polyphen
0.0
B;B
Vest4
0.049
MutPred
0.28
Loss of glycosylation at P323 (P = 0.0411);Loss of glycosylation at P323 (P = 0.0411);
MVP
0.24
MPC
1.1
ClinPred
0.041
T
GERP RS
-8.3
Varity_R
0.019
gMVP
0.25
Mutation Taster
=86/14
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: rs139342764; hg19: chr5-1294033; API