Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1PM2PM5BP4

The NM_198253.3(TERT):c.2081T>C(p.Val694Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000126 in 1,584,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. V694M) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.154

Publications

2 publications found

Variant links:

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

TERT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 24 uncertain 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 chr5-1279341-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12731.

BP4

Computational evidence support a benign effect (MetaRNN=0.38875046).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198253.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TERT	NM_198253.3	MANE Select	c.2081T>C	p.Val694Ala	missense	Exon 5 of 16	NP_937983.2
TERT	NM_001193376.3		c.2081T>C	p.Val694Ala	missense	Exon 5 of 15	NP_001180305.1
TERT	NR_149162.3		n.2160T>C		non_coding_transcript_exon	Exon 5 of 13

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TERT	ENST00000310581.10	TSL:1 MANE Select	c.2081T>C	p.Val694Ala	missense	Exon 5 of 16	ENSP00000309572.5
TERT	ENST00000334602.10	TSL:1	c.2081T>C	p.Val694Ala	missense	Exon 5 of 15	ENSP00000334346.6
TERT	ENST00000460137.6	TSL:1	n.2081T>C		non_coding_transcript_exon	Exon 5 of 13	ENSP00000425003.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.98e-7

AC:

AN:

1432598

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710178

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32856

American (AMR)

AF:

0.00

AC:

AN:

40654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25594

East Asian (EAS)

AF:

0.00

AC:

AN:

38204

South Asian (SAS)

AF:

0.00

AC:

AN:

82068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49978

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4224

European-Non Finnish (NFE)

AF:

9.09e-7

AC:

AN:

1099836

Other (OTH)

AF:

0.00

AC:

AN:

59184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

8.9

(source)

DANN

Benign

0.66

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.58

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.39

MetaSVM

Pathogenic

0.82

MutationAssessor

Benign

1.2

PhyloP100

-0.15

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.34

Sift

Benign

0.078

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.21

MutPred

0.48

Gain of methylation at R691 (P = 0.0962)

MVP

0.79

MPC

1.4

ClinPred

0.19

GERP RS

0.96

Varity_R

0.051

gMVP

0.89

Mutation Taster

=65/35

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs1026167666

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over