5-1272213-G-C

Position:

• chr5-1272213-G-C

Variant summary

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

The ENST00000310581.10(TERT):​c.2354C>G​(p.Pro785Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. P785A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TERT ENST00000310581.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.97

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=0.07507813).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.2354C>G	p.Pro785Arg	missense_variant	7/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2354C>G	p.Pro785Arg	missense_variant	7/15		NP_001180305.1
TERT	NR_149162.3	n.2366-3580C>G		intron_variant, non_coding_transcript_variant
TERT	NR_149163.3	n.2330-3580C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.2354C>G	p.Pro785Arg	missense_variant	7/16	1	NM_198253.3	ENSP00000309572	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 246970 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134522

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460382 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726446

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

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

Aug 17, 2023

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 not 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. ClinVar contains an entry for this variant (Variation ID: 581831). This variant has not been reported in the literature in individuals affected with TERT-related conditions. This variant is present in population databases (rs483352771, gnomAD 0.004%). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 785 of the TERT protein (p.Pro785Arg). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 2024

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Dyskeratosis congenita Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2023

The p.P785R variant (also known as c.2354C>G), located in coding exon 7 of the TERT gene, results from a C to G substitution at nucleotide position 2354. The proline at codon 785 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	0.078
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	15
DANN	Benign	0.14
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.59	T;T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.075	T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	-0.90	N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.3	N;N
REVEL	Benign	0.19
Sift	Benign	0.60	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.053	B;B
Vest4		0.17
MutPred		0.39		Gain of solvent accessibility (P = 0.1045);Gain of solvent accessibility (P = 0.1045);
MVP		0.35
MPC		1.1
ClinPred		0.036	T
GERP RS		3.4
Varity_R		0.041
gMVP		0.46

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: rs483352771; hg19: chr5-1272328;