5-1272285-C-T

Position:

chr5-1272285-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_198253.3(TERT):c.2287-5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000789 in 1,608,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 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 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

TERT
NM_198253.3 splice_region, intron

Scores

Splicing: ADA: 0.2333

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: -6.42

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:

TERT (HGNC:):

TERT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
TERT	NM_198253.3 linkuse as main transcript	c.2287-5G>A	splice_region_variant, intron_variant	ENST00000310581.10	NP_937983.2	O14746-1
TERT	NM_001193376.3 linkuse as main transcript	c.2287-5G>A	splice_region_variant, intron_variant		NP_001180305.1	O14746-3
TERT	NR_149162.3 linkuse as main transcript	n.2366-3652G>A	intron_variant
TERT	NR_149163.3 linkuse as main transcript	n.2330-3652G>A	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10 linkuse as main transcript	c.2287-5G>A		splice_region_variant, intron_variant		1	NM_198253.3	ENSP00000309572.5		O14746-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000130

AC:

AN:

239302

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

130542

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.000115

Gnomad SAS exome

AF:

0.000542

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000648

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.0000789

AC:

115

AN:

1456692

Hom.:

Cov.:

AF XY:

0.0000897

AC XY:

AN XY:

724314

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000113

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.000445

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000567

Gnomad4 OTH exome

AF:

0.0000831

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000959

Hom.:

Bravo

AF:

0.0000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dyskeratosis congenita, autosomal dominant 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 12, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The splice region variant c.2287-5G>A in TERT gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.2287-5G>A variant is present with an allele frequency of 0.01% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Benign/ Uncertain Significance multiple submissions. Splice AI predicts this variant to cause splice acceptor loss 0.02 and splice acceptor gain 0.82. For these reasons, this variant has been classified as Variant of Uncertain Significance VUS. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 05, 2019

- -

Aplastic anemia;C0023467:Acute myeloid leukemia;C3151443:Dyskeratosis congenita, autosomal dominant 2;C3553617:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1;C3554574:Melanoma, cutaneous malignant, susceptibility to, 9;C4551974:Dyskeratosis congenita, autosomal dominant 1;C5561926:Interstitial lung disease 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Degerman lab, Umeå University

Nov 23, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 27, 2023

In silico analysis supports a deleterious effect on splicing; Observed in an individual with congenital kidney disorder, thrombocytopenia, and anemia (PMID: 29483670); This variant is associated with the following publications: (PMID: 29483670) -

Dyskeratosis congenita

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2024

The c.2287-5G>A intronic variant results from a G to A substitution 5 nucleotides upstream from coding exon 7 in the TERT gene. This variant was reported as heterozygous in an individual with features consistent with TERT-related disorder (Norberg A et al. Eur J Hum Genet, 2018 Jun;26:858-867). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, the clinical significance of this variant remains unclear. -

TERT-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2023

The TERT c.2287-5G>A variant is predicted to interfere with splicing. This variant was reported along with a TERT nonsense change in an individual with a congenital kidney disorder, thrombocytopenia, hypocellular bone marrow, and myelodysplastic syndrome or aplastic anemia (Norberg et al. 2018. PubMed ID: 29483670). This variant is reported in 0.054% of alleles in individuals of South Asian descent in gnomAD, which is likely too high to be a cause of autosomal dominant disease (http://gnomad.broadinstitute.org/variant/5-1272400-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

DANN

Benign

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.23

dbscSNV1_RF

Benign

0.46

SpliceAI score (max)

0.82

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.82

Position offset: -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