rs1554043151

Variant names:

• chr5-1294848-G-A
• NM_198253.3:c.142C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-1294848-G-A
• chr5-1294848-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_198253.3(TERT):​c.142C>T​(p.Arg48Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000383 in 1,307,140 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.961

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 RNA-interacting domain 1 (size 229) in uniprot entity TERT_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_198253.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.142C>T	p.Arg48Cys	missense_variant	Exon 1 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.142C>T	p.Arg48Cys	missense_variant	Exon 1 of 15		NP_001180305.1
TERT	NR_149162.3	n.221C>T		non_coding_transcript_exon_variant	Exon 1 of 13
TERT	NR_149163.3	n.221C>T		non_coding_transcript_exon_variant	Exon 1 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.142C>T	p.Arg48Cys	missense_variant	Exon 1 of 16	1	NM_198253.3	ENSP00000309572.5
TERT	ENST00000334602.10	c.142C>T	p.Arg48Cys	missense_variant	Exon 1 of 15	1		ENSP00000334346.6
TERT	ENST00000460137.6	n.142C>T		non_coding_transcript_exon_variant	Exon 1 of 13	1		ENSP00000425003.1
TERT	ENST00000656021.1	n.142C>T		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000499759.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000383 AC: 5 AN: 1307140 Hom.: 0 Cov.: 34 AF XY: 0.00000156 AC XY: 1 AN XY: 642984

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: 0.00000478

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

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

Apr 24, 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. 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: 1431056). This variant has not been reported in the literature in individuals affected with TERT-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 48 of the TERT protein (p.Arg48Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.7	L;L
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.10
MutPred		0.53		Loss of MoRF binding (P = 0.0053);Loss of MoRF binding (P = 0.0053);
MVP		0.96
MPC		1.8
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.41
gMVP		0.56

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: chr5-1294963; COSMIC: COSV57240299;