rs573817924

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_198253.3(TERT):c.219+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000631 in 1,544,544 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00066 ( 1 hom. )

Consequence

TERT
NM_198253.3 splice_region, intron

Scores

Splicing: ADA: 0.00001177

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: -1.24

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 5-1294764-G-A is Benign according to our data. Variant chr5-1294764-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 350805.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1}. Variant chr5-1294764-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
TERT	NM_198253.3 linkuse as main transcript	c.219+7C>T	splice_region_variant, intron_variant	ENST00000310581.10
TERT	NM_001193376.3 linkuse as main transcript	c.219+7C>T	splice_region_variant, intron_variant
TERT	NR_149162.3 linkuse as main transcript	n.298+7C>T	splice_region_variant, intron_variant, non_coding_transcript_variant
TERT	NR_149163.3 linkuse as main transcript	n.298+7C>T	splice_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10 linkuse as main transcript	c.219+7C>T	splice_region_variant, intron_variant	1	NM_198253.3	P2	O14746-1
TERT	ENST00000334602.10 linkuse as main transcript	c.219+7C>T	splice_region_variant, intron_variant	1		A2	O14746-3
TERT	ENST00000460137.6 linkuse as main transcript	c.219+7C>T	splice_region_variant, intron_variant, NMD_transcript_variant	1			O14746-4
TERT	ENST00000656021.1 linkuse as main transcript	c.219+7C>T	splice_region_variant, intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000325

AC:

AN:

141468

Hom.:

AF XY:

0.000318

AC XY:

AN XY:

78526

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000156

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000710

Gnomad OTH exome

AF:

0.000245

GnomAD4 exome

AF:

0.000662

AC:

921

AN:

1392248

Hom.:

Cov.:

AF XY:

0.000613

AC XY:

422

AN XY:

688432

show subpopulations

Gnomad4 AFR exome

AF:

0.0000648

Gnomad4 AMR exome

AF:

0.000214

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000586

Gnomad4 NFE exome

AF:

0.000823

Gnomad4 OTH exome

AF:

0.000258

GnomAD4 genome

AF:

0.000348

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000323

Hom.:

Bravo

AF:

0.000431

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 26, 2017	c.219+7C>T in Intron 1 of TERT: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.07% (46/70754) o f European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad .broadinstitute.org; dbSNP rs573817924). ACMG/AMP Criteria applied: BP4, BP7 (Ri chards 2015). -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Dyskeratosis congenita

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 15, 2014

The c.219+7C>T intronic variant results from a C to T substitution 7 nucleotides after coding exon 1 in the TERT gene. This variant was first identified in a 13 year old female who was diagnosed with Diamond Blackfan anemia at 6 months of age and was transfusion dependent and had telomere lengths below the first percentile; this variant was also identified in her reportedly healthy father, who had telomere lengths near the first percentile. In addition, both carried a promoter variant, c.-171A>T, in the DKC1 gene; however, authors felt neither variant explained the clinical picture of the affected daughter (Pavesi E et al. Pediatr Blood Cancer. 2009;53(3):411-6). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 3491 samples (6982 alleles) with coverage at this position. This nucleotide position is not well conserved in available vertebrate species on limited alignment. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this donor splice site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Aplastic anemia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Dyskeratosis congenita, autosomal dominant 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

TERT-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

5.1

DANN

Benign

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000012

dbscSNV1_RF

Benign

0.0040

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