chr5-1264479-G-A

Variant names:

• chr5-1264479-G-A
• rs387907251
• NM_198253.3:c.2768C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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). Synonymous variant affecting the same amino acid position (i.e. P923P) has been classified as Benign.

• 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
• Publications: 8 publications found

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]

TERT Gene-Disease associations (from GenCC):

• pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• dyskeratosis congenita, autosomal dominant 2

  Inheritance: AR, AD, SD, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• dyskeratosis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hoyeraal-Hreidarsson syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• melanoma, cutaneous malignant, susceptibility to, 9

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId is 36950.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.2768C>T	p.Pro923Leu	missense_variant	Exon 11 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2654+1985C>T		intron_variant	Intron 10 of 14		NP_001180305.1
TERT	NR_149162.3	n.2551+1985C>T		intron_variant	Intron 8 of 12
TERT	NR_149163.3	n.2515+1985C>T		intron_variant	Intron 8 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.2768C>T	p.Pro923Leu	missense_variant	Exon 11 of 16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249260 AF XY: 0.00

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60392

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

Nov 14, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Feb 24, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

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

Apr 19, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dyskeratosis congenita Pathogenic:1

Apr 14, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 13, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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). This variant is present in population databases (rs387907251, gnomAD 0.007%). 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). ClinVar contains an entry for this variant (Variation ID: 36950). 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. -

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
PhyloP100		6.1
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
Mutation Taster		=19/81	disease causing

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

Other links and lift over

dbSNP: rs387907251; hg19: chr5-1264594;