5-1293550-G-T

Variant names:

Variant summary

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

The NM_198253.3(TERT):c.1336C>A(p.Arg446Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,549,050 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R446C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: -0.172

Publications

4 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=0.008676618).

BP6

Variant 5-1293550-G-T is Benign according to our data. Variant chr5-1293550-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242216.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000794 (121/152350) while in subpopulation AFR AF = 0.0026 (108/41592). AF 95% confidence interval is 0.0022. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 34. 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.1336C>A	p.Arg446Ser	missense	Exon 2 of 16	NP_937983.2	O14746-1
TERT	NM_001193376.3		c.1336C>A	p.Arg446Ser	missense	Exon 2 of 15	NP_001180305.1	O14746-3
TERT	NR_149162.3		n.1415C>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.1336C>A	p.Arg446Ser	missense	Exon 2 of 16	ENSP00000309572.5	O14746-1
TERT	ENST00000334602.10	TSL:1	c.1336C>A	p.Arg446Ser	missense	Exon 2 of 15	ENSP00000334346.6	O14746-3
TERT	ENST00000460137.6	TSL:1	n.1336C>A		non_coding_transcript_exon	Exon 2 of 13	ENSP00000425003.1	O14746-4

Frequencies

GnomAD3 genomes

AF:

0.000795

AC:

121

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00260

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000133

AC:

AN:

150400

AF XY:

0.0000868

show subpopulations

Gnomad AFR exome

AF:

0.00220

Gnomad AMR exome

AF:

0.0000812

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000175

Gnomad OTH exome

AF:

0.000235

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1396700

Hom.:

Cov.:

AF XY:

0.0000421

AC XY:

AN XY:

688418

show subpopulations

African (AFR)

AF:

0.00221

AC:

AN:

31642

American (AMR)

AF:

0.000252

AC:

AN:

35722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25068

East Asian (EAS)

AF:

0.00

AC:

AN:

35840

South Asian (SAS)

AF:

0.00

AC:

AN:

79494

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1077512

Other (OTH)

AF:

0.0000864

AC:

AN:

57866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.000794

AC:

121

AN:

152350

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00260

AC:

108

AN:

41592

American (AMR)

AF:

0.000849

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.0000452

Hom.:

Bravo

AF:

0.00107

ExAC

AF:

0.0000763

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Dyskeratosis congenita (2)

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

not specified (1)

TERT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

0.14

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.30

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.59

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.0087

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

1.3

PhyloP100

-0.17

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.28

REVEL

Benign

0.22

Sift

Benign

0.76

Sift4G

Benign

0.90

Polyphen

0.0030

Vest4

0.17

MVP

0.74

MPC

1.2

ClinPred

0.0017

GERP RS

-6.4

Varity_R

0.062

gMVP

0.19

Mutation Taster

=58/42

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