rs7725218

Variant names:

• chr5-1282299-G-A
• rs7725218
• NM_198253.3:c.1769+130C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-1282299-G-A
• chr5-1282299-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_198253.3(TERT):​c.1769+130C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 955,560 control chromosomes in the GnomAD database, including 60,792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.38 (10717 hom., cov: 33)
  • Exomes 𝑓: 0.35 (50075 hom.)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.977
• Publications: 54 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 5-1282299-G-A is Benign according to our data. Variant chr5-1282299-G-A is described in ClinVar as Benign. ClinVar VariationId is 1280138.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.1769+130C>T		intron_variant	Intron 3 of 15	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.1769+130C>T		intron_variant	Intron 3 of 14		NP_001180305.1
TERT	NR_149162.3	n.1848+130C>T		intron_variant	Intron 3 of 12
TERT	NR_149163.3	n.1848+130C>T		intron_variant	Intron 3 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.1769+130C>T		intron_variant	Intron 3 of 15	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes AF: 0.375 AC: 57018 AN: 151948 Hom.: 10704 Cov.: 33

Gnomad AFR AF: 0.432

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.410

GnomAD4 exome AF: 0.349 AC: 280301 AN: 803494 Hom.: 50075 AF XY: 0.352 AC XY: 148187 AN XY: 420532

African (AFR) AF: 0.427 AC: 8827 AN: 20664

American (AMR) AF: 0.292 AC: 10722 AN: 36762

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 8475 AN: 21510

East Asian (EAS) AF: 0.364 AC: 12787 AN: 35126

South Asian (SAS) AF: 0.412 AC: 28490 AN: 69116

European-Finnish (FIN) AF: 0.357 AC: 15952 AN: 44734

Middle Eastern (MID) AF: 0.440 AC: 1316 AN: 2994

European-Non Finnish (NFE) AF: 0.336 AC: 179507 AN: 534032

Other (OTH) AF: 0.369 AC: 14225 AN: 38556

GnomAD4 genome AF: 0.375 AC: 57063 AN: 152066 Hom.: 10717 Cov.: 33 AF XY: 0.373 AC XY: 27714 AN XY: 74346

African (AFR) AF: 0.432 AC: 17915 AN: 41484

American (AMR) AF: 0.318 AC: 4854 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1373 AN: 3466

East Asian (EAS) AF: 0.387 AC: 2000 AN: 5164

South Asian (SAS) AF: 0.415 AC: 1995 AN: 4812

European-Finnish (FIN) AF: 0.356 AC: 3767 AN: 10580

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.351 AC: 23831 AN: 67972

Other (OTH) AF: 0.418 AC: 881 AN: 2110

Alfa AF: 0.357 Hom.: 19355

Bravo AF: 0.375

Asia WGS AF: 0.449 AC: 1564 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.44
DANN	Benign	0.51
PhyloP100		-0.98
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: rs7725218; hg19: chr5-1282414; COSMIC: COSV57204890;