rs1554039732

Positions:

• chr5-1268575-T-C

Variant summary

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

The NM_198253.3(TERT):​c.2527A>G​(p.Ser843Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.75

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 (HGNC:):

ACMG classification

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
TERT	NM_198253.3	c.2527A>G	p.Ser843Gly	missense_variant	9/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2527A>G	p.Ser843Gly	missense_variant	9/15		NP_001180305.1
TERT	NR_149162.3	n.2424A>G		non_coding_transcript_exon_variant	7/13
TERT	NR_149163.3	n.2388A>G		non_coding_transcript_exon_variant	7/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.2527A>G	p.Ser843Gly	missense_variant	9/16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 17, 2017

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TERT-related disease. This sequence change replaces serine with glycine at codon 843 of the TERT protein (p.Ser843Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. -

Dyskeratosis congenita Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2024

The p.S843G variant (also known as c.2527A>G), located in coding exon 9 of the TERT gene, results from an A to G substitution at nucleotide position 2527. The serine at codon 843 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.72
Sift	Benign	0.24	T;D
Sift4G	Benign	0.076	T;D
Polyphen		1.0	D;D
Vest4		0.43
MutPred		0.57		Loss of stability (P = 0.0736);Loss of stability (P = 0.0736);
MVP		0.97
MPC		2.1
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.40
gMVP		0.76

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

Other links and lift over

dbSNP: rs1554039732; hg19: chr5-1268690;