chr5-1253665-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198253.3(TERT):c.*63C>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 0.00217 in 1,435,942 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 32 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 17 hom. )

Consequence

TERT
NM_198253.3 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.25

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 links:

ENSG00000287486 (HGNC:):

ENSG00000287486 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 5-1253665-G-A is Benign according to our data. Variant chr5-1253665-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 350516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0105 (1600/152332) while in subpopulation AFR AF= 0.0359 (1493/41576). AF 95% confidence interval is 0.0344. There are 32 homozygotes in gnomad4. There are 769 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 32 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3 link	c.*63C>T	3_prime_UTR_variant	Exon 16 of 16	ENST00000310581.10	NP_937983.2	O14746-1
TERT	NM_001193376.3 link	c.*63C>T	3_prime_UTR_variant	Exon 15 of 15		NP_001180305.1	O14746-3
TERT	NR_149162.3 link	n.3170C>T	non_coding_transcript_exon_variant	Exon 13 of 13
TERT	NR_149163.3 link	n.3134C>T	non_coding_transcript_exon_variant	Exon 13 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581 link	c.*63C>T		3_prime_UTR_variant	Exon 16 of 16	1	NM_198253.3	ENSP00000309572.5		O14746-1

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1591

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0358

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00366

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.0105

GnomAD4 exome

AF:

0.00118

AC:

1512

AN:

1283610

Hom.:

Cov.:

AF XY:

0.000993

AC XY:

638

AN XY:

642494

show subpopulations

Gnomad4 AFR exome

AF:

0.0369

Gnomad4 AMR exome

AF:

0.00157

Gnomad4 ASJ exome

AF:

0.00475

Gnomad4 EAS exome

AF:

0.000185

Gnomad4 SAS exome

AF:

0.0000634

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000609

Gnomad4 OTH exome

AF:

0.00240

GnomAD4 genome

AF:

0.0105

AC:

1600

AN:

152332

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

769

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0359

Gnomad4 AMR

AF:

0.00359

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00602

Hom.:

Bravo

AF:

0.0122

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aplastic anemia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dyskeratosis congenita, autosomal dominant 2

Benign:1

Jan 13, 2018

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided

Benign:1

Feb 14, 2019

GeneDx

Significance: Likely 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

-0.90

CADD

Benign

0.71

DANN

Benign

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over