rs567650961

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_198253.3(TERT):​c.1336C>T​(p.Arg446Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 1,396,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.172
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.32478607).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TERTNM_198253.3 linkuse as main transcriptc.1336C>T p.Arg446Cys missense_variant 2/16 ENST00000310581.10 NP_937983.2 O14746-1
TERTNM_001193376.3 linkuse as main transcriptc.1336C>T p.Arg446Cys missense_variant 2/15 NP_001180305.1 O14746-3
TERTNR_149162.3 linkuse as main transcriptn.1415C>T non_coding_transcript_exon_variant 2/13
TERTNR_149163.3 linkuse as main transcriptn.1415C>T 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.1336C>T p.Arg446Cys missense_variant 2/161 NM_198253.3 ENSP00000309572.5 O14746-1
TERTENST00000334602.10 linkuse as main transcriptc.1336C>T p.Arg446Cys missense_variant 2/151 ENSP00000334346.6 O14746-3
TERTENST00000460137.6 linkuse as main transcriptn.1336C>T non_coding_transcript_exon_variant 2/131 ENSP00000425003.1 O14746-4
TERTENST00000656021.1 linkuse as main transcriptn.1336C>T non_coding_transcript_exon_variant 2/17 ENSP00000499759.1 A0A590UK92

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
0.00000358
AC:
5
AN:
1396700
Hom.:
0
Cov.:
32
AF XY:
0.00000145
AC XY:
1
AN XY:
688418
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000464
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 10, 2023This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 446 of the TERT protein (p.Arg446Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TERT-related conditions. ClinVar contains an entry for this variant (Variation ID: 1056210). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TERT protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMar 13, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.036
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
10
DANN
Benign
0.96
DEOGEN2
Uncertain
0.48
T;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.039
N
LIST_S2
Benign
0.84
T;T
M_CAP
Pathogenic
0.51
D
MetaRNN
Benign
0.32
T;T
MetaSVM
Uncertain
0.32
D
MutationAssessor
Benign
1.6
L;L
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-1.6
N;N
REVEL
Uncertain
0.42
Sift
Benign
0.056
T;T
Sift4G
Benign
0.076
T;T
Polyphen
0.99
D;D
Vest4
0.20
MutPred
0.44
Gain of catalytic residue at P445 (P = 0.0118);Gain of catalytic residue at P445 (P = 0.0118);
MVP
0.69
MPC
2.2
ClinPred
0.75
D
GERP RS
-6.4
Varity_R
0.058
gMVP
0.27

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: rs567650961; hg19: chr5-1293665; COSMIC: COSV57243503; COSMIC: COSV57243503; API