5-1294797-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_198253.3(TERT):c.193C>A(p.Pro65Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000853 in 1,524,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. P65A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000073 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 0.882

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 5 ACMG points.

• PM1: In a region_of_interest GQ motif (size 139) in uniprot entity TERT_HUMAN there are 20 pathogenic changes around while only 7 benign (74%) in NM_198253.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-1294797-G-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.38128066).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.193C>A	p.Pro65Thr	missense_variant	1/16	ENST00000310581.10
TERT	NM_001193376.3	c.193C>A	p.Pro65Thr	missense_variant	1/15
TERT	NR_149162.3	n.272C>A		non_coding_transcript_exon_variant	1/13
TERT	NR_149163.3	n.272C>A		non_coding_transcript_exon_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.193C>A	p.Pro65Thr	missense_variant	1/16	1	NM_198253.3	P2
TERT	ENST00000334602.10	c.193C>A	p.Pro65Thr	missense_variant	1/15	1		A2
TERT	ENST00000460137.6	c.193C>A	p.Pro65Thr	missense_variant, NMD_transcript_variant	1/13	1
TERT	ENST00000656021.1	c.193C>A	p.Pro65Thr	missense_variant, NMD_transcript_variant	1/17

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152134 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000167 AC: 2 AN: 119432 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66312

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000429

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: 0.00

Gnomad OTH exome AF: 0.000276

GnomAD4 exome AF: 0.00000729 AC: 10 AN: 1372134 Hom.: 0 Cov.: 35 AF XY: 0.00000738 AC XY: 5 AN XY: 677132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000143

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: 0.00000465

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152242 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74432

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pulmonary fibrosis Pathogenic:1

Likely risk allele, no assertion criteria provided

research

Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center

Jun 09, 2022

Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 16, 2023

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 65 of the TERT protein (p.Pro65Thr). This variant is present in population databases (no rsID available, gnomAD 0.009%). This missense change has been observed in individual(s) with aplastic anemia (PMID: 30995915). ClinVar contains an entry for this variant (Variation ID: 471840). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	15
Dann	Benign	0.95
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	-0.068
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	0.91	N;N;N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.14	T;T
Sift4G	Uncertain	0.049	D;T
Polyphen		0.82	P;P
Vest4		0.17
MutPred		0.54		Loss of catalytic residue at P64 (P = 0.0165);Loss of catalytic residue at P64 (P = 0.0165);
MVP		0.78
MPC		1.5
ClinPred		0.19	T
GERP RS		3.1
Varity_R		0.11
gMVP		0.51

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: rs544215765; hg19: chr5-1294912;