NM_198253.3:c.1573+445G>T

Variant names:

• chr5-1292868-C-A
• rs2853672
• NM_198253.3:c.1573+445G>T

Variant summary

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

The NM_198253.3(TERT):​c.1573+445G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 152,032 control chromosomes in the GnomAD database, including 18,486 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 0.49 (18486 hom., cov: 33)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.915
• Publications: 26 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.1573+445G>T		intron_variant	Intron 2 of 15	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.1573+445G>T		intron_variant	Intron 2 of 14		NP_001180305.1
TERT	NR_149162.3	n.1652+445G>T		intron_variant	Intron 2 of 12
TERT	NR_149163.3	n.1652+445G>T		intron_variant	Intron 2 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.1573+445G>T		intron_variant	Intron 2 of 15	1	NM_198253.3	ENSP00000309572.5
TERT	ENST00000334602.10	c.1573+445G>T		intron_variant	Intron 2 of 14	1		ENSP00000334346.6
TERT	ENST00000460137.6	n.1573+445G>T		intron_variant	Intron 2 of 12	1		ENSP00000425003.1
TERT	ENST00000656021.1	n.*197+96G>T		intron_variant	Intron 2 of 16			ENSP00000499759.1

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74571 AN: 151914 Hom.: 18470 Cov.: 33

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.478

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.526

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.460

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

GnomAD4 genome AF: 0.491 AC: 74628 AN: 152032 Hom.: 18486 Cov.: 33 AF XY: 0.493 AC XY: 36619 AN XY: 74308

African (AFR) AF: 0.473 AC: 19617 AN: 41466

American (AMR) AF: 0.585 AC: 8939 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1288 AN: 3470

East Asian (EAS) AF: 0.527 AC: 2718 AN: 5160

South Asian (SAS) AF: 0.350 AC: 1692 AN: 4828

European-Finnish (FIN) AF: 0.530 AC: 5599 AN: 10556

Middle Eastern (MID) AF: 0.305 AC: 89 AN: 292

European-Non Finnish (NFE) AF: 0.490 AC: 33292 AN: 67954

Other (OTH) AF: 0.455 AC: 959 AN: 2110

Alfa AF: 0.484 Hom.: 60334

Bravo AF: 0.498

Asia WGS AF: 0.434 AC: 1509 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.32
DANN	Benign	0.68
PhyloP100		-0.92
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2853672; hg19: chr5-1292983;