rs2736099

Variant names:

• chr5-1287225-A-G
• rs2736099
• NM_198253.3:c.1574-4601T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198253.3(TERT):​c.1574-4601T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 152,012 control chromosomes in the GnomAD database, including 38,154 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.70 (38154 hom., cov: 31)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.576
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

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

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• dyskeratosis congenita, autosomal dominant 2

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

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.823 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.1574-4601T>C		intron_variant	Intron 2 of 15	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.1574-4601T>C		intron_variant	Intron 2 of 14		NP_001180305.1
TERT	NR_149162.3	n.1653-4601T>C		intron_variant	Intron 2 of 12
TERT	NR_149163.3	n.1653-4601T>C		intron_variant	Intron 2 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.1574-4601T>C		intron_variant	Intron 2 of 15	1	NM_198253.3	ENSP00000309572.5
TERT	ENST00000334602.10	c.1574-4601T>C		intron_variant	Intron 2 of 14	1		ENSP00000334346.6
TERT	ENST00000460137.6	n.1574-4601T>C		intron_variant	Intron 2 of 12	1		ENSP00000425003.1
TERT	ENST00000656021.1	n.*198-139T>C		intron_variant	Intron 2 of 16			ENSP00000499759.1

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106725 AN: 151894 Hom.: 38100 Cov.: 31

Gnomad AFR AF: 0.830

Gnomad AMI AF: 0.712

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.599

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.658

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

GnomAD4 genome AF: 0.703 AC: 106836 AN: 152012 Hom.: 38154 Cov.: 31 AF XY: 0.700 AC XY: 52032 AN XY: 74280

African (AFR) AF: 0.831 AC: 34449 AN: 41474

American (AMR) AF: 0.733 AC: 11184 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 2077 AN: 3470

East Asian (EAS) AF: 0.570 AC: 2949 AN: 5172

South Asian (SAS) AF: 0.534 AC: 2561 AN: 4794

European-Finnish (FIN) AF: 0.677 AC: 7147 AN: 10564

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.651 AC: 44262 AN: 67956

Other (OTH) AF: 0.652 AC: 1375 AN: 2110

Alfa AF: 0.657 Hom.: 26237

Bravo AF: 0.714

Asia WGS AF: 0.548 AC: 1910 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.6
DANN	Benign	0.33
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2736099; hg19: chr5-1287340;