chr5-1253629-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_198253.3(TERT):c.*99C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 998,776 control chromosomes in the GnomAD database, including 16,193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3360 hom., cov: 33)

Exomes 𝑓: 0.16 ( 12833 hom. )

Consequence

TERT
NM_198253.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.49

Publications

26 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:

ENSG00000287486 (HGNC:):

ENSG00000287486 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BP6

Variant 5-1253629-G-A is Benign according to our data. Variant chr5-1253629-G-A is described in ClinVar as [Benign]. Clinvar id is 350515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3 link	c.*99C>T	3_prime_UTR_variant	Exon 16 of 16	ENST00000310581.10	NP_937983.2	O14746-1
TERT	NR_149162.3 link	n.3206C>T	non_coding_transcript_exon_variant	Exon 13 of 13
TERT	NR_149163.3 link	n.3170C>T	non_coding_transcript_exon_variant	Exon 13 of 13
TERT	NM_001193376.3 link	c.*99C>T	3_prime_UTR_variant	Exon 15 of 15		NP_001180305.1	O14746-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10 link	c.*99C>T		3_prime_UTR_variant	Exon 16 of 16	1	NM_198253.3	ENSP00000309572.5		O14746-1

Frequencies

GnomAD3 genomes

AF:

0.193

AC:

29371

AN:

152112

Hom.:

3357

Cov.:

show subpopulations

Gnomad AFR

AF:

0.303

Gnomad AMI

AF:

0.158

Gnomad AMR

AF:

0.141

Gnomad ASJ

AF:

0.127

Gnomad EAS

AF:

0.00384

Gnomad SAS

AF:

0.0849

Gnomad FIN

AF:

0.0902

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.181

Gnomad OTH

AF:

0.180

GnomAD4 exome

AF:

0.162

AC:

137406

AN:

846546

Hom.:

12833

Cov.:

AF XY:

0.158

AC XY:

69096

AN XY:

437754

show subpopulations

African (AFR)

AF:

0.314

AC:

6857

AN:

21860

American (AMR)

AF:

0.0989

AC:

3459

AN:

34966

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

2756

AN:

21480

East Asian (EAS)

AF:

0.00160

AC:

AN:

34304

South Asian (SAS)

AF:

0.0870

AC:

5967

AN:

68614

European-Finnish (FIN)

AF:

0.0977

AC:

3782

AN:

38714

Middle Eastern (MID)

AF:

0.141

AC:

436

AN:

3098

European-Non Finnish (NFE)

AF:

0.184

AC:

107503

AN:

583446

Other (OTH)

AF:

0.165

AC:

6591

AN:

40064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

6363

12726

19090

25453

31816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.193

AC:

29409

AN:

152230

Hom.:

3360

Cov.:

AF XY:

0.186

AC XY:

13858

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.303

AC:

12571

AN:

41516

American (AMR)

AF:

0.140

AC:

2145

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.127

AC:

441

AN:

3470

East Asian (EAS)

AF:

0.00366

AC:

AN:

5192

South Asian (SAS)

AF:

0.0857

AC:

414

AN:

4828

European-Finnish (FIN)

AF:

0.0902

AC:

958

AN:

10620

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.181

AC:

12305

AN:

67988

Other (OTH)

AF:

0.178

AC:

376

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1199

2397

3596

4794

5993

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.180

Hom.:

3855

Bravo

AF:

0.202

Asia WGS

AF:

0.0560

AC:

197

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 08, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

Aplastic anemia

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Dyskeratosis congenita, autosomal dominant 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.18

(source)

DANN

Benign

0.54

PhyloP100

-1.5

Mutation Taster

=100/0

polymorphism (auto)

(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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chr5-1253629-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over