chr5-1280013-T-C

Variant names:

• chr5-1280013-T-C
• rs7734992
• NM_198253.3:c.1950+145A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_198253.3(TERT):​c.1950+145A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,079,128 control chromosomes in the GnomAD database, including 102,532 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18906 hom., cov: 34)
  • Exomes 𝑓: 0.42 (83626 hom.)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.819
• Publications: 22 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 -16 ACMG points.

• BP6: Variant 5-1280013-T-C is Benign according to our data. Variant chr5-1280013-T-C is described in ClinVar as Benign. ClinVar VariationId is 1267625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.1950+145A>G		intron_variant	Intron 4 of 15	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.1950+145A>G		intron_variant	Intron 4 of 14		NP_001180305.1
TERT	NR_149162.3	n.2029+145A>G		intron_variant	Intron 4 of 12
TERT	NR_149163.3	n.2029+145A>G		intron_variant	Intron 4 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.1950+145A>G		intron_variant	Intron 4 of 15	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes AF: 0.487 AC: 74016 AN: 152026 Hom.: 18867 Cov.: 34

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.459

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.489

GnomAD4 exome AF: 0.419 AC: 388845 AN: 926984 Hom.: 83626 AF XY: 0.418 AC XY: 199137 AN XY: 476470

African (AFR) AF: 0.668 AC: 15453 AN: 23126

American (AMR) AF: 0.308 AC: 12385 AN: 40196

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 9611 AN: 21058

East Asian (EAS) AF: 0.374 AC: 13725 AN: 36670

South Asian (SAS) AF: 0.399 AC: 27822 AN: 69798

European-Finnish (FIN) AF: 0.458 AC: 20903 AN: 45682

Middle Eastern (MID) AF: 0.455 AC: 1488 AN: 3272

European-Non Finnish (NFE) AF: 0.417 AC: 269055 AN: 644830

Other (OTH) AF: 0.435 AC: 18403 AN: 42352

GnomAD4 genome AF: 0.487 AC: 74109 AN: 152144 Hom.: 18906 Cov.: 34 AF XY: 0.482 AC XY: 35877 AN XY: 74382

African (AFR) AF: 0.666 AC: 27638 AN: 41486

American (AMR) AF: 0.373 AC: 5706 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 1625 AN: 3468

East Asian (EAS) AF: 0.398 AC: 2057 AN: 5164

South Asian (SAS) AF: 0.397 AC: 1917 AN: 4834

European-Finnish (FIN) AF: 0.459 AC: 4867 AN: 10598

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.422 AC: 28704 AN: 67990

Other (OTH) AF: 0.496 AC: 1048 AN: 2114

Alfa AF: 0.436 Hom.: 6227

Bravo AF: 0.488

Asia WGS AF: 0.455 AC: 1585 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	7.7
DANN	Benign	0.35
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7734992; hg19: chr5-1280128; COSMIC: COSV57212982;