Genetic Variant TERT:c.1950+145A>G (chr5-1280013-T-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_198253.3(TERT):c.1950+145A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,079,128 control chromosomes in the GnomAD database, including 102,532 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 18906 hom., cov: 34)

Exomes 𝑓: 0.42 ( 83626 hom. )

Consequence

TERT
NM_198253.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.819

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 5-1280013-T-C is Benign according to our data. Variant chr5-1280013-T-C is described in ClinVar as [Benign]. Clinvar id is 1267625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3 link	c.1950+145A>G	intron_variant	Intron 4 of 15	ENST00000310581.10	NP_937983.2	O14746-1
TERT	NM_001193376.3 link	c.1950+145A>G	intron_variant	Intron 4 of 14		NP_001180305.1	O14746-3
TERT	NR_149162.3 link	n.2029+145A>G	intron_variant	Intron 4 of 12
TERT	NR_149163.3 link	n.2029+145A>G	intron_variant	Intron 4 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10 link	c.1950+145A>G		intron_variant	Intron 4 of 15	1	NM_198253.3	ENSP00000309572.5		O14746-1

Frequencies

GnomAD3 genomes

AF:

0.487

AC:

74016

AN:

152026

Hom.:

18867

Cov.:

show subpopulations

Gnomad AFR

AF:

0.666

Gnomad AMI

AF:

0.434

Gnomad AMR

AF:

0.374

Gnomad ASJ

AF:

0.469

Gnomad EAS

AF:

0.399

Gnomad SAS

AF:

0.398

Gnomad FIN

AF:

0.459

Gnomad MID

AF:

0.513

Gnomad NFE

AF:

0.422

Gnomad OTH

AF:

0.489

GnomAD4 exome

AF:

0.419

AC:

388845

AN:

926984

Hom.:

83626

AF XY:

0.418

AC XY:

199137

AN XY:

476470

show subpopulations

Gnomad4 AFR exome

AF:

0.668

Gnomad4 AMR exome

AF:

0.308

Gnomad4 ASJ exome

AF:

0.456

Gnomad4 EAS exome

AF:

0.374

Gnomad4 SAS exome

AF:

0.399

Gnomad4 FIN exome

AF:

0.458

Gnomad4 NFE exome

AF:

0.417

Gnomad4 OTH exome

AF:

0.435

GnomAD4 genome

AF:

0.487

AC:

74109

AN:

152144

Hom.:

18906

Cov.:

AF XY:

0.482

AC XY:

35877

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.666

Gnomad4 AMR

AF:

0.373

Gnomad4 ASJ

AF:

0.469

Gnomad4 EAS

AF:

0.398

Gnomad4 SAS

AF:

0.397

Gnomad4 FIN

AF:

0.459

Gnomad4 NFE

AF:

0.422

Gnomad4 OTH

AF:

0.496

Alfa

AF:

0.448

Hom.:

3565

Bravo

AF:

0.488

Asia WGS

AF:

0.455

AC:

1585

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 14, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

7.7

DANN

Benign

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.26

Position offset: 0

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