rs1060503008

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_198253.3(TERT):​c.1211C>T​(p.Pro404Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 34)

Consequence

TERT
NM_198253.3 missense

Scores

7
8
4

Clinical Significance

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

Conservation

PhyloP100: 3.13
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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TERTNM_198253.3 linkc.1211C>T p.Pro404Leu missense_variant Exon 2 of 16 ENST00000310581.10 NP_937983.2 O14746-1
TERTNM_001193376.3 linkc.1211C>T p.Pro404Leu missense_variant Exon 2 of 15 NP_001180305.1 O14746-3
TERTNR_149162.3 linkn.1290C>T non_coding_transcript_exon_variant Exon 2 of 13
TERTNR_149163.3 linkn.1290C>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.1211C>T p.Pro404Leu missense_variant Exon 2 of 16 1 NM_198253.3 ENSP00000309572.5 O14746-1
TERTENST00000334602.10 linkc.1211C>T p.Pro404Leu missense_variant Exon 2 of 15 1 ENSP00000334346.6 O14746-3
TERTENST00000460137.6 linkn.1211C>T non_coding_transcript_exon_variant Exon 2 of 13 1 ENSP00000425003.1 O14746-4
TERTENST00000656021.1 linkn.1211C>T non_coding_transcript_exon_variant Exon 2 of 17 ENSP00000499759.1 A0A590UK92

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
32
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
Nov 23, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 404 of the TERT protein (p.Pro404Leu). This variant is not present in population databases (gnomAD no frequency). 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. 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. This variant has not been reported in the literature in individuals affected with TERT-related conditions. -

Dyskeratosis congenita Uncertain:1
Nov 17, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.P404L variant (also known as c.1211C>T), located in coding exon 2 of the TERT gene, results from a C to T substitution at nucleotide position 1211. The proline at codon 404 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.060
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D;.
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.32
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.85
D
MetaRNN
Pathogenic
0.83
D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Uncertain
2.9
M;M
PrimateAI
Uncertain
0.52
T
PROVEAN
Pathogenic
-5.1
D;D
REVEL
Pathogenic
0.77
Sift
Benign
0.12
T;T
Sift4G
Benign
0.20
T;D
Polyphen
1.0
D;D
Vest4
0.41
MutPred
0.52
Gain of helix (P = 0.027);Gain of helix (P = 0.027);
MVP
0.91
MPC
2.2
ClinPred
1.0
D
GERP RS
3.5
Varity_R
0.16
gMVP
0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-1293790; API