rs1554043124

Positions:

• chr5-1294790-G-A

Variant summary

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

The NM_198253.3(TERT):​c.200C>T​(p.Ala67Val) 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. 14/21 in silico tools predict 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. A67P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 1.41

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 2 ACMG points.

• PM1: In a region_of_interest GQ motif (size 139) in uniprot entity TERT_HUMAN there are 19 pathogenic changes around while only 7 benign (73%) in NM_198253.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21720037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.200C>T	p.Ala67Val	missense_variant	1/16	ENST00000310581.10
TERT	NM_001193376.3	c.200C>T	p.Ala67Val	missense_variant	1/15
TERT	NR_149162.3	n.279C>T		non_coding_transcript_exon_variant	1/13
TERT	NR_149163.3	n.279C>T		non_coding_transcript_exon_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.200C>T	p.Ala67Val	missense_variant	1/16	1	NM_198253.3	P2
TERT	ENST00000334602.10	c.200C>T	p.Ala67Val	missense_variant	1/15	1		A2
TERT	ENST00000460137.6	c.200C>T	p.Ala67Val	missense_variant, NMD_transcript_variant	1/13	1
TERT	ENST00000656021.1	c.200C>T	p.Ala67Val	missense_variant, NMD_transcript_variant	1/17

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1376338 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 679550

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hepatocellular carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

case-control

Metabolic Liver Diseases Lab, Fondazione IRCCS Ca Granda Policlinico, University of Milan

Jun 01, 2016

unstable protein in vitro -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 11, 2021

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. Experimental studies have shown that this variant affects TERT protein function (PMID: 28677271). This variant has been observed in individual(s) with nonalcoholic fatty liver disease - hepatocellular carcinoma (NAFLD-HCC) (PMID: 28677271). ClinVar contains an entry for this variant (Variation ID: 268077). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces alanine with valine at codon 67 of the TERT protein (p.Ala67Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Uncertain	0.46	T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.66	T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.21
Sift	Benign	0.20	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.010	B;B
Vest4		0.074
MutPred		0.34		Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);
MVP		0.75
MPC		1.0
ClinPred		0.052	T
GERP RS		-0.79
Varity_R		0.080
gMVP		0.27

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: rs1554043124; hg19: chr5-1294905;