chr5-1255326-C-T

Position:

• chr5-1255326-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_198253.3(TERT):​c.3118G>A​(p.Ala1040Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.01

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a region_of_interest CTE (size 196) in uniprot entity TERT_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) in NM_198253.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-1255326-C-T is Pathogenic according to our data. Variant chr5-1255326-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1485756.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.3118G>A	p.Ala1040Thr	missense_variant	14/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2929G>A	p.Ala977Thr	missense_variant	13/15		NP_001180305.1
TERT	NR_149162.3	n.2826G>A		non_coding_transcript_exon_variant	11/13
TERT	NR_149163.3	n.2790G>A		non_coding_transcript_exon_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.3118G>A	p.Ala1040Thr	missense_variant	14/16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 30, 2021

This missense change has been observed in individual(s) with clinical features of TERT-related conditions (Invitae). It has also been observed to segregate with disease in related individuals. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 1040 of the TERT protein (p.Ala1040Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. -

Telomere syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

The Telomere Center at Johns Hopkins, Johns Hopkins University School of Medicine

Aug 01, 2022

Classified as pathogenic based on short telomere length in the proband with IPF and bone marrow failure and segregation in the family with short telomere length by flowFISH and expert opinion -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	0.12
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.77	T;T
M_CAP	Pathogenic	0.67	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.35
MutPred		0.41		Loss of MoRF binding (P = 0.3309);.;
MVP		0.90
MPC		2.0
ClinPred		0.94	D
GERP RS		3.8
Varity_R		0.36
gMVP		0.40

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-1255441;