rs1334806555

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The ENST00000310581.10(TERT):​c.892T>A​(p.Ser298Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000317 in 1,575,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S298C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

TERT
ENST00000310581.10 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -2.10
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.078858614).
BP6
Variant 5-1293994-A-T is Benign according to our data. Variant chr5-1293994-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 539200.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TERTNM_198253.3 linkuse as main transcriptc.892T>A p.Ser298Thr missense_variant 2/16 ENST00000310581.10 NP_937983.2
TERTNM_001193376.3 linkuse as main transcriptc.892T>A p.Ser298Thr missense_variant 2/15 NP_001180305.1
TERTNR_149162.3 linkuse as main transcriptn.971T>A non_coding_transcript_exon_variant 2/13
TERTNR_149163.3 linkuse as main transcriptn.971T>A non_coding_transcript_exon_variant 2/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TERTENST00000310581.10 linkuse as main transcriptc.892T>A p.Ser298Thr missense_variant 2/161 NM_198253.3 ENSP00000309572 P2O14746-1
TERTENST00000334602.10 linkuse as main transcriptc.892T>A p.Ser298Thr missense_variant 2/151 ENSP00000334346 A2O14746-3
TERTENST00000460137.6 linkuse as main transcriptc.892T>A p.Ser298Thr missense_variant, NMD_transcript_variant 2/131 ENSP00000425003 O14746-4
TERTENST00000656021.1 linkuse as main transcriptc.892T>A p.Ser298Thr missense_variant, NMD_transcript_variant 2/17 ENSP00000499759

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152164
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
GnomAD3 exomes
AF:
0.0000106
AC:
2
AN:
187918
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
102002
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000684
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS 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:
0.00000281
AC:
4
AN:
1423742
Hom.:
0
Cov.:
35
AF XY:
0.00000283
AC XY:
2
AN XY:
705708
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000994
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152164
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Dyskeratosis congenita Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 31, 2022The p.S298T variant (also known as c.892T>A), located in coding exon 2 of the TERT gene, results from a T to A substitution at nucleotide position 892. The serine at codon 298 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 09, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
1.0
DANN
Benign
0.78
DEOGEN2
Benign
0.38
T;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.046
N
LIST_S2
Benign
0.46
T;T
M_CAP
Uncertain
0.23
D
MetaRNN
Benign
0.079
T;T
MetaSVM
Uncertain
0.093
D
MutationAssessor
Benign
0.83
L;L
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-0.76
N;N
REVEL
Benign
0.16
Sift
Benign
0.21
T;T
Sift4G
Benign
0.19
T;T
Polyphen
0.0080
B;B
Vest4
0.089
MutPred
0.32
Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);
MVP
0.76
MPC
1.0
ClinPred
0.063
T
GERP RS
0.49
Varity_R
0.053
gMVP
0.25

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1334806555; hg19: chr5-1294109; API