chr5-1279913-G-A

Variant names:

• chr5-1279913-G-A
• rs2242652
• NM_198253.3:c.1950+245C>T

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.1950+245C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 152,150 control chromosomes in the GnomAD database, including 2,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.18 (2398 hom., cov: 33)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.61
• Publications: 149 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: 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=-1.03).
• BP6: Variant 5-1279913-G-A is Benign according to our data. Variant chr5-1279913-G-A is described in ClinVar as Benign. ClinVar VariationId is 539266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.193 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.1950+245C>T		intron	N/A	NP_937983.2	O14746-1
	TERT	NM_001193376.3		c.1950+245C>T		intron	N/A	NP_001180305.1	O14746-3
	TERT	NR_149162.3		n.2029+245C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.1950+245C>T		intron	N/A	ENSP00000309572.5	O14746-1
	TERT	ENST00000334602.10	TSL:1	c.1950+245C>T		intron	N/A	ENSP00000334346.6	O14746-3
	TERT	ENST00000460137.6	TSL:1	n.1950+245C>T		intron	N/A	ENSP00000425003.1	O14746-4

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26806 AN: 152032 Hom.: 2399 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.207

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

GnomAD4 genome AF: 0.176 AC: 26800 AN: 152150 Hom.: 2398 Cov.: 33 AF XY: 0.176 AC XY: 13112 AN XY: 74386

African (AFR) AF: 0.132 AC: 5482 AN: 41544

American (AMR) AF: 0.155 AC: 2372 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 756 AN: 3472

East Asian (EAS) AF: 0.174 AC: 900 AN: 5160

South Asian (SAS) AF: 0.182 AC: 876 AN: 4826

European-Finnish (FIN) AF: 0.225 AC: 2384 AN: 10578

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.196 AC: 13340 AN: 67964

Other (OTH) AF: 0.205 AC: 433 AN: 2112

Alfa AF: 0.189 Hom.: 5499

Bravo AF: 0.169

Asia WGS AF: 0.183 AC: 640 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.80
DANN	Benign	0.62
PhyloP100		-1.6
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: rs2242652; hg19: chr5-1280028; COSMIC: COSV57205318;