NM_198253.3:c.3386C>A

Variant names:

• chr5-1253741-G-T
• rs775095158
• NM_198253.3:c.3386C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_198253.3(TERT):​c.3386C>A​(p.Thr1129Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. T1129S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.881
• Publications: 0 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

ENSG00000287486 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32896122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.3386C>A	p.Thr1129Asn	missense_variant	Exon 16 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.3197C>A	p.Thr1066Asn	missense_variant	Exon 15 of 15		NP_001180305.1
TERT	NR_149162.3	n.3094C>A		non_coding_transcript_exon_variant	Exon 13 of 13
TERT	NR_149163.3	n.3058C>A		non_coding_transcript_exon_variant	Exon 13 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.3386C>A	p.Thr1129Asn	missense_variant	Exon 16 of 16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Dec 12, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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 variant has not been reported in the literature in individuals with TERT-related conditions. This sequence change replaces threonine with asparagine at codon 1129 of the TERT protein (p.Thr1129Asn). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and asparagine. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.6	M;.
PhyloP100		0.88
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.018	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.99	D;B
Vest4		0.20
MutPred		0.15		Loss of phosphorylation at T1129 (P = 0.0271);.;
MVP		0.92
MPC		1.7
ClinPred		0.48	T
GERP RS		0.97
Varity_R		0.10
gMVP		0.45
Mutation Taster		=77/23	polymorphism

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: rs775095158; hg19: chr5-1253856;