rs4975605

Variant names:

• chr5-1275413-C-A
• rs4975605
• NM_198253.3:c.2287-3133G>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.2287-3133G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 149,290 control chromosomes in the GnomAD database, including 13,504 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 0.42 (13504 hom., cov: 29)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.40
• Publications: 31 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.2287-3133G>T		intron_variant	Intron 6 of 15	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2287-3133G>T		intron_variant	Intron 6 of 14		NP_001180305.1
TERT	NR_149162.3	n.2365+3228G>T		intron_variant	Intron 6 of 12
TERT	NR_149163.3	n.2329+3228G>T		intron_variant	Intron 6 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.2287-3133G>T		intron_variant	Intron 6 of 15	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes AF: 0.419 AC: 62579 AN: 149184 Hom.: 13503 Cov.: 29

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.419

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

GnomAD4 genome AF: 0.419 AC: 62596 AN: 149290 Hom.: 13504 Cov.: 29 AF XY: 0.408 AC XY: 29793 AN XY: 72944

African (AFR) AF: 0.426 AC: 16804 AN: 39416

American (AMR) AF: 0.343 AC: 5189 AN: 15134

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 1504 AN: 3464

East Asian (EAS) AF: 0.117 AC: 603 AN: 5170

South Asian (SAS) AF: 0.340 AC: 1623 AN: 4772

European-Finnish (FIN) AF: 0.369 AC: 3806 AN: 10316

Middle Eastern (MID) AF: 0.382 AC: 110 AN: 288

European-Non Finnish (NFE) AF: 0.466 AC: 31584 AN: 67746

Other (OTH) AF: 0.413 AC: 857 AN: 2074

Alfa AF: 0.449 Hom.: 17325

Bravo AF: 0.424

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.88
DANN	Benign	0.30
PhyloP100		1.4
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: rs4975605; hg19: chr5-1275528;