NM_198253.3:c.-245T>C

Variant names:

• chr5-1295234-A-G
• rs2853669
• ENST00000771252.1:n.45+51A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198253.3(TERT):​c.-245T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 151,924 control chromosomes in the GnomAD database, including 5,628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.25 (5628 hom., cov: 34)
• Consequence: TERT NM_198253.3 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.887
• Publications: 200 publications found

Genes affected

ENSG00000300381 (HGNC:):

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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• dyskeratosis congenita, autosomal dominant 2

  Inheritance: Unknown, SD, AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen, Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 5-1295234-A-G is Benign according to our data. Variant chr5-1295234-A-G is described in ClinVar as Benign. ClinVar VariationId is 539240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198253.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	NM_198253.3	MANE Select	c.-245T>C		upstream_gene	N/A	NP_937983.2	O14746-1
	TERT	NM_001193376.3		c.-245T>C		upstream_gene	N/A	NP_001180305.1	O14746-3
	TERT	NR_149162.3		n.-166T>C		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000300381	ENST00000771252.1		n.45+51A>G		intron	N/A
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.-245T>C		upstream_gene	N/A	ENSP00000309572.5	O14746-1
	TERT	ENST00000334602.10	TSL:1	c.-245T>C		upstream_gene	N/A	ENSP00000334346.6	O14746-3

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38580 AN: 151816 Hom.: 5623 Cov.: 34

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.284

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.254 AC: 38593 AN: 151924 Hom.: 5628 Cov.: 34 AF XY: 0.255 AC XY: 18952 AN XY: 74272

African (AFR) AF: 0.124 AC: 5128 AN: 41500

American (AMR) AF: 0.236 AC: 3605 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1241 AN: 3466

East Asian (EAS) AF: 0.367 AC: 1878 AN: 5118

South Asian (SAS) AF: 0.529 AC: 2552 AN: 4826

European-Finnish (FIN) AF: 0.226 AC: 2395 AN: 10574

Middle Eastern (MID) AF: 0.366 AC: 107 AN: 292

European-Non Finnish (NFE) AF: 0.306 AC: 20748 AN: 67846

Other (OTH) AF: 0.293 AC: 619 AN: 2112

Alfa AF: 0.299 Hom.: 9440

Bravo AF: 0.246

Asia WGS AF: 0.442 AC: 1523 AN: 3456

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	3.9
DANN	Benign	0.064
PhyloP100		-0.89
PromoterAI		0.020	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2853669; hg19: chr5-1295349; COSMIC: COSV57201510;