rs1388515349

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198253.3(TERT):​c.2227C>T​(p.Arg743Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

3
7
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.08
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TERTNM_198253.3 linkuse as main transcriptc.2227C>T p.Arg743Trp missense_variant 6/16 ENST00000310581.10 NP_937983.2 O14746-1
TERTNM_001193376.3 linkuse as main transcriptc.2227C>T p.Arg743Trp missense_variant 6/15 NP_001180305.1 O14746-3
TERTNR_149162.3 linkuse as main transcriptn.2306C>T non_coding_transcript_exon_variant 6/13
TERTNR_149163.3 linkuse as main transcriptn.2270C>T non_coding_transcript_exon_variant 6/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TERTENST00000310581.10 linkuse as main transcriptc.2227C>T p.Arg743Trp missense_variant 6/161 NM_198253.3 ENSP00000309572.5 O14746-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251476
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
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:
0.00000205
AC:
3
AN:
1461812
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 04, 2024In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24833766, 33709208) -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicDec 31, 2019- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 27, 2019- -
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 30, 2021This sequence change replaces arginine with tryptophan at codon 743 of the TERT protein (p.Arg743Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with premature greying of the hair, coronary artery disease and myelodysplastic syndrome (PMID: 24833766). ClinVar contains an entry for this variant (Variation ID: 436991). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.014
T
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.90
D;.
Eigen
Benign
-0.44
Eigen_PC
Benign
-0.46
FATHMM_MKL
Benign
0.18
N
LIST_S2
Uncertain
0.89
D;D
M_CAP
Pathogenic
0.55
D
MetaRNN
Uncertain
0.59
D;D
MetaSVM
Uncertain
0.45
D
MutationAssessor
Uncertain
2.1
M;M
PrimateAI
Benign
0.22
T
PROVEAN
Pathogenic
-4.6
D;D
REVEL
Uncertain
0.37
Sift
Benign
0.11
T;T
Sift4G
Benign
0.087
T;T
Polyphen
0.20
B;B
Vest4
0.46
MutPred
0.55
Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);
MVP
0.64
MPC
1.3
ClinPred
0.68
D
GERP RS
4.6
Varity_R
0.18
gMVP
0.90

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: rs1388515349; hg19: chr5-1278815; COSMIC: COSV57224146; API