5-1260508-C-T

Position:

• chr5-1260508-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_198253.3(TERT):​c.2936G>A​(p.Arg979Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R979W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 1.48

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 4 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-1260509-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.18676063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.2936G>A	p.Arg979Gln	missense_variant	12/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2747G>A	p.Arg916Gln	missense_variant	11/15		NP_001180305.1
TERT	NR_149162.3	n.2644G>A		non_coding_transcript_exon_variant	9/13
TERT	NR_149163.3	n.2608G>A		non_coding_transcript_exon_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.2936G>A	p.Arg979Gln	missense_variant	12/16	1	NM_198253.3	ENSP00000309572	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461820 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 04, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 26, 2017	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg979Gln variant in TERT has been reported in one individual with features of dyskeratos is congenita and in an unaffected parent (Collopy 2015). It has also been identi fied in 1/111716 European chromosomes by the Genome Aggregation Database (gnomAD , http://gnomad.broadinstitute.org; dbSNP rs765566930). In vitro functional stud ies show that the variant results in reduced telomerase activity which is at 35% of that observed in wild type cells (Collopy 2015). Computational prediction to ols and conservation analysis provide conflicting predictions on impact of the v ariant to the protein. Splice prediction tools suggest creation of a novel crypt ic splice site that may impact normal splicing; however, glutamine (Gln) at this position is also present 3 mammals (cow, sheep, and antelope), raising the poss ibility that this change may be tolerated. In summary, while there is some suspi cion for a pathogenic role, the clinical significance of the p.Arg979Gln variant is uncertain. ACMG/AMP Criteria applied: PM2; PS4_Supporting. -

Dyskeratosis congenita, autosomal dominant 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Aug 06, 2019

This TERT variant (rs765566930) is rare (<0.1%) in one large population dataset and absent from another (ExAC: 1/120770 total alleles; 0.000008%; no homozygotes). A single submitter in ClinVar classifies this variant as a variant of uncertain clinical significance. This variant has been reported in a patient with clinical findings consistent with dyskeratosis congenita, and functional studies suggest that this substitution may impact telomerase activity. The arginine reside at this position is predicted to be in the TERT nuclear export signal. An alternate missense change at this position (p.Arg979Trp) has been identified in a patient with aplastic anemia and may affect telomerase function. If the patient meets the clinical diagnostic criteria for telomere shortening disorders, c.2936G>A is likely the molecular cause of to disease9. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 979 of the TERT protein (p.Arg979Gln). This variant is present in population databases (rs765566930, gnomAD 0.0009%). This missense change has been observed in individual(s) with dyskeratosis congenita (PMID: 26024875). ClinVar contains an entry for this variant (Variation ID: 506255). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TERT function (PMID: 26024875). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.10
Sift	Benign	0.10	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.94	P;B
Vest4		0.20
MutPred		0.51		Loss of methylation at R979 (P = 0.0123);.;
MVP		0.77
MPC		1.6
ClinPred		0.66	D
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
gMVP		0.47

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: rs765566930; hg19: chr5-1260623;