rs1554043124

Variant names:

• chr5-1294790-G-A
• rs1554043124
• NM_198253.3:c.200C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. 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. 15/22 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
• Publications: 1 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• 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 rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.200C>T	p.Ala67Val	missense_variant	Exon 1 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.200C>T	p.Ala67Val	missense_variant	Exon 1 of 15		NP_001180305.1
TERT	NR_149162.3	n.279C>T		non_coding_transcript_exon_variant	Exon 1 of 13
TERT	NR_149163.3	n.279C>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.200C>T	p.Ala67Val	missense_variant	Exon 1 of 16	1	NM_198253.3	ENSP00000309572.5
TERT	ENST00000334602.10	c.200C>T	p.Ala67Val	missense_variant	Exon 1 of 15	1		ENSP00000334346.6
TERT	ENST00000460137.6	n.200C>T		non_coding_transcript_exon_variant	Exon 1 of 13	1		ENSP00000425003.1
TERT	ENST00000656021.1	n.200C>T		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000499759.1

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

African (AFR) AF: 0.00 AC: 0 AN: 29722

American (AMR) AF: 0.00 AC: 0 AN: 35328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24580

East Asian (EAS) AF: 0.00 AC: 0 AN: 34964

South Asian (SAS) AF: 0.00 AC: 0 AN: 78510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4108

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078084

Other (OTH) AF: 0.00 AC: 0 AN: 57446

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

Jun 01, 2016

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

unstable protein in vitro -

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

May 11, 2021

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. 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
PhyloP100		1.4
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
PromoterAI		-0.0048	Neutral
Varity_R		0.080
gMVP		0.27
Mutation Taster		=67/33	disease causing (ClinVar)

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: rs1554043124; hg19: chr5-1294905;