5-1272247-G-C

Variant names:

• chr5-1272247-G-C
• NM_198253.3:c.2320C>G

Variant summary

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

The NM_198253.3(TERT):​c.2320C>G​(p.Arg774Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0920

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=0.11293256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.2320C>G	p.Arg774Gly	missense_variant	Exon 7 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2320C>G	p.Arg774Gly	missense_variant	Exon 7 of 15		NP_001180305.1
TERT	NR_149162.3	n.2366-3614C>G		intron_variant	Intron 6 of 12
TERT	NR_149163.3	n.2330-3614C>G		intron_variant	Intron 6 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.2320C>G	p.Arg774Gly	missense_variant	Exon 7 of 16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460416 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726474

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dyskeratosis congenita Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R774G variant (also known as c.2320C>G), located in coding exon 7 of the TERT gene, results from a C to G substitution at nucleotide position 2320. The arginine at codon 774 is replaced by glycine, 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. 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	0.090
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.1
DANN	Benign	0.79
DEOGEN2	Uncertain	0.52	D;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.66	T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.63	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.26
Sift	Benign	0.21	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.0030	B;B
Vest4		0.16
MutPred		0.55		Gain of loop (P = 0.0195);Gain of loop (P = 0.0195);
MVP		0.36
MPC		1.3
ClinPred		0.081	T
GERP RS		-2.8
Varity_R		0.12
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr5-1272362;