rs4246742

Variant names:

• chr5-1267241-T-A
• rs4246742
• NM_198253.3:c.2583-706A>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.2583-706A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 152,040 control chromosomes in the GnomAD database, including 4,748 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 0.23 (4748 hom., cov: 33)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.119
• Publications: 36 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.2583-706A>T		intron_variant	Intron 9 of 15	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2583-706A>T		intron_variant	Intron 9 of 14		NP_001180305.1
TERT	NR_149162.3	n.2480-706A>T		intron_variant	Intron 7 of 12
TERT	NR_149163.3	n.2444-706A>T		intron_variant	Intron 7 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.2583-706A>T		intron_variant	Intron 9 of 15	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34950 AN: 151922 Hom.: 4723 Cov.: 33

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.195

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

GnomAD4 genome AF: 0.230 AC: 35030 AN: 152040 Hom.: 4748 Cov.: 33 AF XY: 0.236 AC XY: 17565 AN XY: 74318

African (AFR) AF: 0.334 AC: 13847 AN: 41474

American (AMR) AF: 0.206 AC: 3140 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 491 AN: 3470

East Asian (EAS) AF: 0.389 AC: 2012 AN: 5168

South Asian (SAS) AF: 0.140 AC: 672 AN: 4812

European-Finnish (FIN) AF: 0.337 AC: 3556 AN: 10560

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10705 AN: 67970

Other (OTH) AF: 0.205 AC: 433 AN: 2108

Alfa AF: 0.204 Hom.: 502

Bravo AF: 0.228

Asia WGS AF: 0.305 AC: 1057 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.1
DANN	Benign	0.56
PhyloP100		-0.12
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: rs4246742; hg19: chr5-1267356;