rs2075786

Variant names:

• chr5-1266195-A-G
• rs2075786
• NM_198253.3:c.2654+269T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-1266195-A-G
• chr5-1266195-A-C

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.2654+269T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 152,090 control chromosomes in the GnomAD database, including 23,749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.54 (23749 hom., cov: 33)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.74
• Publications: 40 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BP6: Variant 5-1266195-A-G is Benign according to our data. Variant chr5-1266195-A-G is described in ClinVar as Benign. ClinVar VariationId is 539247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.646 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.2654+269T>C		intron	N/A	NP_937983.2	O14746-1
	TERT	NM_001193376.3		c.2654+269T>C		intron	N/A	NP_001180305.1	O14746-3
	TERT	NR_149162.3		n.2551+269T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.2654+269T>C		intron	N/A	ENSP00000309572.5	O14746-1
	TERT	ENST00000334602.10	TSL:1	c.2654+269T>C		intron	N/A	ENSP00000334346.6	O14746-3
	TERT	ENST00000460137.6	TSL:1	n.*48+269T>C		intron	N/A	ENSP00000425003.1	O14746-4

Frequencies

GnomAD3 genomes AF: 0.545 AC: 82848 AN: 151972 Hom.: 23754 Cov.: 33

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.465

Gnomad ASJ AF: 0.612

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.579

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

GnomAD4 genome AF: 0.545 AC: 82867 AN: 152090 Hom.: 23749 Cov.: 33 AF XY: 0.535 AC XY: 39783 AN XY: 74356

African (AFR) AF: 0.446 AC: 18508 AN: 41486

American (AMR) AF: 0.464 AC: 7106 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 2124 AN: 3472

East Asian (EAS) AF: 0.191 AC: 985 AN: 5148

South Asian (SAS) AF: 0.508 AC: 2453 AN: 4828

European-Finnish (FIN) AF: 0.519 AC: 5497 AN: 10592

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.651 AC: 44214 AN: 67944

Other (OTH) AF: 0.574 AC: 1214 AN: 2116

Alfa AF: 0.630 Hom.: 24548

Bravo AF: 0.534

Asia WGS AF: 0.350 AC: 1221 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.082
DANN	Benign	0.084
PhyloP100		-4.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2075786; hg19: chr5-1266310;