5-1268585-C-T

Variant names:

• chr5-1268585-C-T
• rs140124989
• NM_198253.3:c.2517G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_198253.3(TERT):​c.2517G>A​(p.Thr839Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,613,422 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T839T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (14 hom.)
• Consequence: TERT NM_198253.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.36
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.176).
• BP6: Variant 5-1268585-C-T is Benign according to our data. Variant chr5-1268585-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00194 (295/152358) while in subpopulation SAS AF = 0.0058 (28/4828). AF 95% confidence interval is 0.00412. There are 2 homozygotes in GnomAd4. There are 165 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,Unknown,SD,AR gene

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.2517G>A	p.Thr839Thr	synonymous	Exon 9 of 16	NP_937983.2	O14746-1
	TERT	NM_001193376.3		c.2517G>A	p.Thr839Thr	synonymous	Exon 9 of 15	NP_001180305.1	O14746-3
	TERT	NR_149162.3		n.2414G>A		non_coding_transcript_exon	Exon 7 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.2517G>A	p.Thr839Thr	synonymous	Exon 9 of 16	ENSP00000309572.5	O14746-1
	TERT	ENST00000334602.10	TSL:1	c.2517G>A	p.Thr839Thr	synonymous	Exon 9 of 15	ENSP00000334346.6	O14746-3
	TERT	ENST00000460137.6	TSL:1	n.2299G>A		non_coding_transcript_exon	Exon 7 of 13	ENSP00000425003.1	O14746-4

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152240 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00715

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00282 AC: 706 AN: 250212 AF XY: 0.00314

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00699

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00712

Gnomad NFE exome AF: 0.00202

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00237 AC: 3460 AN: 1461064 Hom.: 14 Cov.: 31 AF XY: 0.00253 AC XY: 1841 AN XY: 726792

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000403 AC: 18 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00784 AC: 205 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00786 AC: 678 AN: 86256

European-Finnish (FIN) AF: 0.00593 AC: 312 AN: 52636

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5768

European-Non Finnish (NFE) AF: 0.00182 AC: 2026 AN: 1111982

Other (OTH) AF: 0.00288 AC: 174 AN: 60386

GnomAD4 genome AF: 0.00194 AC: 295 AN: 152358 Hom.: 2 Cov.: 33 AF XY: 0.00221 AC XY: 165 AN XY: 74496

African (AFR) AF: 0.000361 AC: 15 AN: 41588

American (AMR) AF: 0.00105 AC: 16 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4828

European-Finnish (FIN) AF: 0.00715 AC: 76 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00188 AC: 128 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00198 Hom.: 0

Bravo AF: 0.00134

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00202

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Dyskeratosis congenita (2)
-	-	2	Dyskeratosis congenita, autosomal dominant 2 (2)
-	-	2	not specified (2)
-	-	1	Acute myeloid leukemia (1)
-	-	1	Aplastic anemia (1)
-	-	1	Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 (1)
-	-	1	Melanoma, cutaneous malignant, susceptibility to, 9 (1)
-	-	1	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_noAF	Uncertain	0.12
CADD	Benign	0.15
DANN	Benign	0.95
PhyloP100		-1.4
Mutation Taster		=98/2	polymorphism

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: rs140124989; hg19: chr5-1268700; COSMIC: COSV104395555;