rs121918661

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_198253.3(TERT):c.604G>A(p.Ala202Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,594,112 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. A202V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:16B:5O:1

Conservation

PhyloP100: -1.97

Publications

23 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
dyskeratosis congenita, autosomal dominant 2
Inheritance: Unknown, SD, AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen, Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
acute myeloid leukemia
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

TERT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01952967).

BP6

Variant 5-1294282-C-T is Benign according to our data. Variant chr5-1294282-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12729.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000147 (212/1441744) while in subpopulation MID AF = 0.00594 (34/5720). AF 95% confidence interval is 0.00437. There are 1 homozygotes in GnomAdExome4. There are 125 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.

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	UniProt
TERT	NM_198253.3	MANE Select	c.604G>A	p.Ala202Thr	missense	Exon 2 of 16	NP_937983.2	O14746-1
TERT	NM_001193376.3		c.604G>A	p.Ala202Thr	missense	Exon 2 of 15	NP_001180305.1	O14746-3
TERT	NR_149162.3		n.683G>A		non_coding_transcript_exon	Exon 2 of 13

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TERT	ENST00000310581.10	TSL:1 MANE Select	c.604G>A	p.Ala202Thr	missense	Exon 2 of 16	ENSP00000309572.5	O14746-1
TERT	ENST00000334602.10	TSL:1	c.604G>A	p.Ala202Thr	missense	Exon 2 of 15	ENSP00000334346.6	O14746-3
TERT	ENST00000460137.6	TSL:1	n.604G>A		non_coding_transcript_exon	Exon 2 of 13	ENSP00000425003.1	O14746-4

Frequencies

GnomAD3 genomes

AF:

0.000190

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000316

AC:

AN:

208938

AF XY:

0.000240

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.000877

Gnomad ASJ exome

AF:

0.000431

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000162

Gnomad OTH exome

AF:

0.00206

GnomAD4 exome

AF:

0.000147

AC:

212

AN:

1441744

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

125

AN XY:

717266

show subpopulations

African (AFR)

AF:

0.000300

AC:

AN:

33298

American (AMR)

AF:

0.000910

AC:

AN:

43972

Ashkenazi Jewish (ASJ)

AF:

0.000270

AC:

AN:

25904

East Asian (EAS)

AF:

0.00

AC:

AN:

39298

South Asian (SAS)

AF:

0.000153

AC:

AN:

85048

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40116

Middle Eastern (MID)

AF:

0.00594

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.0000586

AC:

AN:

1108512

Other (OTH)

AF:

0.000718

AC:

AN:

59876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.000190

AC:

AN:

152368

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41592

American (AMR)

AF:

0.000522

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000671

Hom.:

Bravo

AF:

0.000355

ESP6500AA

AF:

0.000476

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000229

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Dyskeratosis congenita, autosomal dominant 2 (4)

not specified (4)

Dyskeratosis congenita (2)

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 (2)

Aplastic anemia (2)

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

TERT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

2.4

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.31

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.53

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.020

MetaSVM

Uncertain

0.10

MutationAssessor

Benign

0.0

PhyloP100

-2.0

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.23

REVEL

Uncertain

0.55

Sift

Benign

0.56

Sift4G

Benign

0.61

Polyphen

0.18

Vest4

0.50

MVP

0.98

MPC

1.0

ClinPred

0.0071

GERP RS

0.90

Varity_R

0.047

gMVP

0.71

Mutation Taster

=80/20

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over