rs13167280

Variant names:

• chr5-1280362-G-A
• rs13167280
• NM_198253.3:c.1770-24C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-1280362-G-A
• chr5-1280362-G-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.1770-24C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,609,006 control chromosomes in the GnomAD database, including 13,259 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1122 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12137 hom.)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0530
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-1280362-G-A is Benign according to our data. Variant chr5-1280362-G-A is described in ClinVar as Benign. ClinVar VariationId is 1274097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.197 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	NM_198253.3	MANE Select	c.1770-24C>T		intron	N/A	NP_937983.2
	TERT	NM_001193376.3		c.1770-24C>T		intron	N/A	NP_001180305.1
	TERT	NR_149162.3		n.1849-24C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.1770-24C>T		intron	N/A	ENSP00000309572.5
	TERT	ENST00000334602.10	TSL:1	c.1770-24C>T		intron	N/A	ENSP00000334346.6
	TERT	ENST00000460137.6	TSL:1	n.1770-24C>T		intron	N/A	ENSP00000425003.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16304 AN: 152132 Hom.: 1106 Cov.: 33

Gnomad AFR AF: 0.0357

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.0956

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.127 AC: 31040 AN: 243860 AF XY: 0.126

Gnomad AFR exome AF: 0.0324

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.209

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.135

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.126 AC: 183570 AN: 1456754 Hom.: 12137 Cov.: 32 AF XY: 0.126 AC XY: 91120 AN XY: 724744

African (AFR) AF: 0.0328 AC: 1098 AN: 33432

American (AMR) AF: 0.112 AC: 4993 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 3325 AN: 26096

East Asian (EAS) AF: 0.160 AC: 6328 AN: 39648

South Asian (SAS) AF: 0.100 AC: 8606 AN: 86074

European-Finnish (FIN) AF: 0.156 AC: 7926 AN: 50850

Middle Eastern (MID) AF: 0.156 AC: 754 AN: 4840

European-Non Finnish (NFE) AF: 0.129 AC: 143076 AN: 1111078

Other (OTH) AF: 0.124 AC: 7464 AN: 60174

GnomAD4 genome AF: 0.107 AC: 16342 AN: 152252 Hom.: 1122 Cov.: 33 AF XY: 0.107 AC XY: 7943 AN XY: 74432

African (AFR) AF: 0.0360 AC: 1497 AN: 41566

American (AMR) AF: 0.109 AC: 1672 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 448 AN: 3470

East Asian (EAS) AF: 0.208 AC: 1074 AN: 5168

South Asian (SAS) AF: 0.0963 AC: 465 AN: 4828

European-Finnish (FIN) AF: 0.151 AC: 1598 AN: 10602

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9116 AN: 68012

Other (OTH) AF: 0.135 AC: 286 AN: 2112

Alfa AF: 0.127 Hom.: 1374

Bravo AF: 0.103

Asia WGS AF: 0.179 AC: 621 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.4
DANN	Benign	0.35
PhyloP100		-0.053
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs13167280; hg19: chr5-1280477; COSMIC: COSV57198812;