rs904848231

Positions:

• chr5-1293840-G-A
• chr5-1293840-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198253.3(TERT):​c.1046C>T​(p.Ser349Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,396,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S349C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.361

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25109696).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.1046C>T	p.Ser349Phe	missense_variant	2/16	ENST00000310581.10
TERT	NM_001193376.3	c.1046C>T	p.Ser349Phe	missense_variant	2/15
TERT	NR_149162.3	n.1125C>T		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.1125C>T		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.1046C>T	p.Ser349Phe	missense_variant	2/16	1	NM_198253.3	P2
TERT	ENST00000334602.10	c.1046C>T	p.Ser349Phe	missense_variant	2/15	1		A2
TERT	ENST00000460137.6	c.1046C>T	p.Ser349Phe	missense_variant, NMD_transcript_variant	2/13	1
TERT	ENST00000656021.1	c.1046C>T	p.Ser349Phe	missense_variant, NMD_transcript_variant	2/17

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1396260 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 688854

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

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: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

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

Oct 16, 2023

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 349 of the TERT protein (p.Ser349Phe). 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: 840092). 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. 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 submitter

clinical testing

Baylor Genetics

Sep 23, 2023

- -

Dyskeratosis congenita Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2022

The p.S349F variant (also known as c.1046C>T), located in coding exon 2 of the TERT gene, results from a C to T substitution at nucleotide position 1046. The serine at codon 349 is replaced by phenylalanine, an amino acid with highly dissimilar 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. -

TERT-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2024

The TERT c.1046C>T variant is predicted to result in the amino acid substitution p.Ser349Phe. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is classified as a variant of uncertain significance by multiple submitters in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/840092/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.56	T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.9	M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.23
Sift	Uncertain	0.020	D;D
Sift4G	Uncertain	0.028	D;D
Polyphen		0.98	D;B
Vest4		0.10
MVP		0.50
MPC		1.2
ClinPred		0.12	T
GERP RS		-2.1
Varity_R		0.14
gMVP		0.44

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: rs904848231; hg19: chr5-1293955;