5-1293493-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_198253.3(TERT):c.1393G>A(p.Val465Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V465L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91

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 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_198253.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4099371).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.1393G>A	p.Val465Met	missense_variant	2/16	ENST00000310581.10
TERT	NM_001193376.3	c.1393G>A	p.Val465Met	missense_variant	2/15
TERT	NR_149162.3	n.1472G>A		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.1472G>A		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.1393G>A	p.Val465Met	missense_variant	2/16	1	NM_198253.3	P2
TERT	ENST00000334602.10	c.1393G>A	p.Val465Met	missense_variant	2/15	1		A2
TERT	ENST00000460137.6	c.1393G>A	p.Val465Met	missense_variant, NMD_transcript_variant	2/13	1
TERT	ENST00000656021.1	c.1393G>A	p.Val465Met	missense_variant, NMD_transcript_variant	2/17

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435296 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 711926

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: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.73	N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		0.99	D;D
Vest4		0.37
MutPred		0.44		Gain of phosphorylation at Y462 (P = 0.1822);Gain of phosphorylation at Y462 (P = 0.1822);
MVP		0.80
MPC		2.1
ClinPred		0.71	D
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.33
gMVP		0.47

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: rs758110675; hg19: chr5-1293608;