rs2853677

Variant names:

• chr5-1287079-G-A
• rs2853677
• NM_198253.3:c.1574-4455C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-1287079-G-A
• chr5-1287079-G-C
• chr5-1287079-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.1574-4455C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 151,954 control chromosomes in the GnomAD database, including 30,173 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.63 (30173 hom., cov: 31)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.614
• Publications: 155 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 5-1287079-G-A is Benign according to our data. Variant chr5-1287079-G-A is described in ClinVar as Benign. ClinVar VariationId is 1167534.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.719 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	NM_198253.3	MANE Select	c.1574-4455C>T		intron	N/A	NP_937983.2	O14746-1
	TERT	NM_001193376.3		c.1574-4455C>T		intron	N/A	NP_001180305.1	O14746-3
	TERT	NR_149162.3		n.1653-4455C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.1574-4455C>T		intron	N/A	ENSP00000309572.5	O14746-1
	TERT	ENST00000334602.10	TSL:1	c.1574-4455C>T		intron	N/A	ENSP00000334346.6	O14746-3
	TERT	ENST00000460137.6	TSL:1	n.1574-4455C>T		intron	N/A	ENSP00000425003.1	O14746-4

Frequencies

GnomAD3 genomes AF: 0.625 AC: 94938 AN: 151838 Hom.: 30129 Cov.: 31

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.668

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.577

Gnomad OTH AF: 0.561

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

GnomAD4 genome AF: 0.625 AC: 95029 AN: 151954 Hom.: 30173 Cov.: 31 AF XY: 0.625 AC XY: 46437 AN XY: 74244

African (AFR) AF: 0.726 AC: 30068 AN: 41424

American (AMR) AF: 0.669 AC: 10207 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 1660 AN: 3466

East Asian (EAS) AF: 0.629 AC: 3252 AN: 5172

South Asian (SAS) AF: 0.447 AC: 2152 AN: 4814

European-Finnish (FIN) AF: 0.631 AC: 6657 AN: 10552

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.577 AC: 39224 AN: 67946

Other (OTH) AF: 0.555 AC: 1169 AN: 2106

Alfa AF: 0.591 Hom.: 94577

Bravo AF: 0.637

Asia WGS AF: 0.514 AC: 1791 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.60
PhyloP100		-0.61
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: rs2853677; hg19: chr5-1287194;