5-1285859-C-A

Variant names:

• chr5-1285859-C-A
• rs7705526
• NM_198253.3:c.1574-3235G>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.1574-3235G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 151,526 control chromosomes in the GnomAD database, including 6,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.29 (6736 hom., cov: 29)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.498
• Publications: 114 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=-0.96).
• BP6: Variant 5-1285859-C-A is Benign according to our data. Variant chr5-1285859-C-A is described in ClinVar as Benign. ClinVar VariationId is 539227.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.1574-3235G>T		intron_variant	Intron 2 of 15	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.1574-3235G>T		intron_variant	Intron 2 of 14		NP_001180305.1
TERT	NR_149162.3	n.1653-3235G>T		intron_variant	Intron 2 of 12
TERT	NR_149163.3	n.1653-3235G>T		intron_variant	Intron 2 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.1574-3235G>T		intron_variant	Intron 2 of 15	1	NM_198253.3	ENSP00000309572.5
TERT	ENST00000334602.10	c.1574-3235G>T		intron_variant	Intron 2 of 14	1		ENSP00000334346.6
TERT	ENST00000460137.6	n.1574-3235G>T		intron_variant	Intron 2 of 12	1		ENSP00000425003.1
TERT	ENST00000656021.1	n.*1119+306G>T		intron_variant	Intron 3 of 16			ENSP00000499759.1

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44209 AN: 151408 Hom.: 6729 Cov.: 29

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.349

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

GnomAD4 genome AF: 0.292 AC: 44226 AN: 151526 Hom.: 6736 Cov.: 29 AF XY: 0.291 AC XY: 21553 AN XY: 74004

African (AFR) AF: 0.187 AC: 7734 AN: 41326

American (AMR) AF: 0.279 AC: 4243 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 1312 AN: 3460

East Asian (EAS) AF: 0.392 AC: 1996 AN: 5094

South Asian (SAS) AF: 0.422 AC: 2024 AN: 4794

European-Finnish (FIN) AF: 0.313 AC: 3275 AN: 10468

Middle Eastern (MID) AF: 0.455 AC: 133 AN: 292

European-Non Finnish (NFE) AF: 0.331 AC: 22477 AN: 67874

Other (OTH) AF: 0.356 AC: 749 AN: 2106

Alfa AF: 0.317 Hom.: 13061

Bravo AF: 0.284

Asia WGS AF: 0.435 AC: 1512 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.96
CADD	Benign	0.27
DANN	Benign	0.57
PhyloP100		-0.50
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: rs7705526; hg19: chr5-1285974;