rs387907251

Positions:

• chr5-1264479-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_198253.3(TERT):​c.2768C>T​(p.Pro923Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3
• Conservation: PhyloP100: 6.09

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 5-1264479-G-A is Pathogenic according to our data. Variant chr5-1264479-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36950.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.2768C>T	p.Pro923Leu	missense_variant	11/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2654+1985C>T		intron_variant			NP_001180305.1
TERT	NR_149162.3	n.2551+1985C>T		intron_variant, non_coding_transcript_variant
TERT	NR_149163.3	n.2515+1985C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.2768C>T	p.Pro923Leu	missense_variant	11/16	1	NM_198253.3	ENSP00000309572	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249260 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135346

Gnomad AFR exome AF: 0.0000646

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461558 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727090

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000594 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 24, 2020	This sequence change has been reported in the gnomAD database in one individual (dbSNP rs387907251). This sequence change has been identified in an individual with telomere-related pulmonary fibrosis and bone marrow failure. This patient was reported to have a family history consistent with TERT-related disorders, including pulmonary fibrosis, thrombocytopenia, and acute myeloid leukemia; however, affected relatives were not analyzed for this sequence change (PMID: 22512499). The p.Pro923Leu change affects a highly conserved amino acid residue located in a domain of the TERT protein that is known to be functional. The p.Pro923Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in patients with a personal and/or family history of a TERT-related disorder and shortened telomeres (PMID: 23618685, 29976374); This variant is associated with the following publications: (PMID: 26642856, 23618685, 22512499, 29976374, 33203829, 31256854, 25393420) -

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 19, 2012

- -

Dyskeratosis congenita Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 2022

The p.P923L variant (also known as c.2768C>T), located in coding exon 11 of the TERT gene, results from a C to T substitution at nucleotide position 2768. The proline at codon 923 is replaced by leucine, an amino acid with similar properties. This variant was first described in an individual with idiopathic pulmonary fibrosis, mild pancytopenia, and short telomere lengths. This individual's family history was remarkable for a parent and 3 siblings with pulmonary fibrosis; two siblings also had thrombocytopenia and acute myeloid leukemia, respectively (Gansner JM et al. N. Engl. J. Med., 2012 Apr;366:1551-3). In addition, this variant was described in a second individual with idiopathic pulmonary fibrosis and hypocellularity on bone marrow biopsy who was listed for lung transplantation (George G et al. Chest, 2015 Jun;147:1549-1557). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 13, 2024

Variant summary: TERT c.2768C>T (p.Pro923Leu) results in a non-conservative amino acid change located in the Reverse transcriptase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249260 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2768C>T has been reported in the literature in individuals affected with TERT-Related Disorders (Gansner_2012, Stark_2022, Ferrer_2023). These report(s) do not provide unequivocal conclusions about association of the variant with TERT-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37665761, 22512499, 35083318). ClinVar contains an entry for this variant (Variation ID: 36950). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 07, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 36950). This missense change has been observed in individual(s) with diffuse pulmonary fibrosis. However, it is uncertain if the variant is of germline or somatic origin (PMID: 22512499). This variant is present in population databases (rs387907251, gnomAD 0.007%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 923 of the TERT protein (p.Pro923Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.56		Loss of relative solvent accessibility (P = 0.0071);
MVP		0.95
MPC		1.6
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.86

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: rs387907251; hg19: chr5-1264594;